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  • 1
    Publication Date: 2015-03-31
    Description: In response to adenosine 5'-diphosphate, the P2Y1 receptor (P2Y1R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y1R in complex with a nucleotide antagonist MRS2500 at 2.7 A resolution, and with a non-nucleotide antagonist BPTU at 2.2 A resolution. The structures reveal two distinct ligand-binding sites, providing atomic details of P2Y1R's unique ligand-binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y1R, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2Y12R, representative of another P2YR subfamily. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G-protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolution insights into P2Y1R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408927/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408927/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Dandan -- Gao, Zhan-Guo -- Zhang, Kaihua -- Kiselev, Evgeny -- Crane, Steven -- Wang, Jiang -- Paoletta, Silvia -- Yi, Cuiying -- Ma, Limin -- Zhang, Wenru -- Han, Gye Won -- Liu, Hong -- Cherezov, Vadim -- Katritch, Vsevolod -- Jiang, Hualiang -- Stevens, Raymond C -- Jacobson, Kenneth A -- Zhao, Qiang -- Wu, Beili -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54GM094618/GM/NIGMS NIH HHS/ -- Z01 DK031116-21/Intramural NIH HHS/ -- Z01DK031116-26/DK/NIDDK NIH HHS/ -- ZIA DK031116-26/Intramural NIH HHS/ -- England -- Nature. 2015 Apr 16;520(7547):317-21. doi: 10.1038/nature14287. Epub 2015 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA. ; Bridge Institute, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA. ; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; 1] Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA [2] Bridge Institute, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA [3] iHuman Institute, ShanghaiTech University, 99 Haike Road, Pudong, Shanghai 201203, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25822790" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/analogs & derivatives/chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Deoxyadenine Nucleotides/*chemistry/*metabolism/pharmacology ; Humans ; Ligands ; Models, Molecular ; Molecular Conformation ; Purinergic P2Y Receptor Antagonists/*chemistry/metabolism/pharmacology ; Receptors, Purinergic P2Y1/*chemistry/*metabolism ; Thionucleotides/chemistry/metabolism ; Uracil/*analogs & derivatives/chemistry/metabolism/pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2010-07-03
    Description: Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18x per individual. Genes showing population-specific allele frequency changes, which represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1), a transcription factor involved in response to hypoxia. One single-nucleotide polymorphism (SNP) at EPAS1 shows a 78% frequency difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP's association with erythrocyte abundance supports the role of EPAS1 in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus in genetic adaptation to high altitude.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711608/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711608/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yi, Xin -- Liang, Yu -- Huerta-Sanchez, Emilia -- Jin, Xin -- Cuo, Zha Xi Ping -- Pool, John E -- Xu, Xun -- Jiang, Hui -- Vinckenbosch, Nicolas -- Korneliussen, Thorfinn Sand -- Zheng, Hancheng -- Liu, Tao -- He, Weiming -- Li, Kui -- Luo, Ruibang -- Nie, Xifang -- Wu, Honglong -- Zhao, Meiru -- Cao, Hongzhi -- Zou, Jing -- Shan, Ying -- Li, Shuzheng -- Yang, Qi -- Asan -- Ni, Peixiang -- Tian, Geng -- Xu, Junming -- Liu, Xiao -- Jiang, Tao -- Wu, Renhua -- Zhou, Guangyu -- Tang, Meifang -- Qin, Junjie -- Wang, Tong -- Feng, Shuijian -- Li, Guohong -- Huasang -- Luosang, Jiangbai -- Wang, Wei -- Chen, Fang -- Wang, Yading -- Zheng, Xiaoguang -- Li, Zhuo -- Bianba, Zhuoma -- Yang, Ge -- Wang, Xinping -- Tang, Shuhui -- Gao, Guoyi -- Chen, Yong -- Luo, Zhen -- Gusang, Lamu -- Cao, Zheng -- Zhang, Qinghui -- Ouyang, Weihan -- Ren, Xiaoli -- Liang, Huiqing -- Zheng, Huisong -- Huang, Yebo -- Li, Jingxiang -- Bolund, Lars -- Kristiansen, Karsten -- Li, Yingrui -- Zhang, Yong -- Zhang, Xiuqing -- Li, Ruiqiang -- Li, Songgang -- Yang, Huanming -- Nielsen, Rasmus -- Wang, Jun -- Wang, Jian -- R01 HG003229/HG/NHGRI NIH HHS/ -- R01 MH084695/MH/NIMH NIH HHS/ -- R01HG003229/HG/NHGRI NIH HHS/ -- R01MHG084695/PHS HHS/ -- New York, N.Y. -- Science. 2010 Jul 2;329(5987):75-8. doi: 10.1126/science.1190371.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉BGI-Shenzhen, Shenzhen 518083, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20595611" target="_blank"〉PubMed〈/a〉
    Keywords: Acclimatization/*genetics ; *Altitude ; Asian Continental Ancestry Group/genetics ; Basic Helix-Loop-Helix Transcription Factors/*genetics/physiology ; Bayes Theorem ; China ; Erythrocyte Count ; Ethnic Groups/genetics ; *Exons ; Female ; Gene Frequency ; Genetic Association Studies ; *Genome, Human ; Hemoglobins/analysis ; Humans ; Male ; Oxygen/blood ; Polymorphism, Single Nucleotide ; *Selection, Genetic ; Sequence Analysis, DNA ; Tibet
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2014-07-22
    Description: As modern humans migrated out of Africa, they encountered many new environmental conditions, including greater temperature extremes, different pathogens and higher altitudes. These diverse environments are likely to have acted as agents of natural selection and to have led to local adaptations. One of the most celebrated examples in humans is the adaptation of Tibetans to the hypoxic environment of the high-altitude Tibetan plateau. A hypoxia pathway gene, EPAS1, was previously identified as having the most extreme signature of positive selection in Tibetans, and was shown to be associated with differences in haemoglobin concentration at high altitude. Re-sequencing the region around EPAS1 in 40 Tibetan and 40 Han individuals, we find that this gene has a highly unusual haplotype structure that can only be convincingly explained by introgression of DNA from Denisovan or Denisovan-related individuals into humans. Scanning a larger set of worldwide populations, we find that the selected haplotype is only found in Denisovans and in Tibetans, and at very low frequency among Han Chinese. Furthermore, the length of the haplotype, and the fact that it is not found in any other populations, makes it unlikely that the haplotype sharing between Tibetans and Denisovans was caused by incomplete ancestral lineage sorting rather than introgression. Our findings illustrate that admixture with other hominin species has provided genetic variation that helped humans to adapt to new environments.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134395/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134395/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huerta-Sanchez, Emilia -- Jin, Xin -- Asan -- Bianba, Zhuoma -- Peter, Benjamin M -- Vinckenbosch, Nicolas -- Liang, Yu -- Yi, Xin -- He, Mingze -- Somel, Mehmet -- Ni, Peixiang -- Wang, Bo -- Ou, Xiaohua -- Huasang -- Luosang, Jiangbai -- Cuo, Zha Xi Ping -- Li, Kui -- Gao, Guoyi -- Yin, Ye -- Wang, Wei -- Zhang, Xiuqing -- Xu, Xun -- Yang, Huanming -- Li, Yingrui -- Wang, Jian -- Wang, Jun -- Nielsen, Rasmus -- R01 HG003229/HG/NHGRI NIH HHS/ -- R01HG003229/HG/NHGRI NIH HHS/ -- R01HG003229-08S2/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Aug 14;512(7513):194-7. doi: 10.1038/nature13408. Epub 2014 Jul 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] BGI-Shenzhen, Shenzhen 518083, China [2] Department of Integrative Biology, University of California, Berkeley, California 94720 USA [3] School of Natural Sciences, University of California, Merced, California 95343 USA [4]. ; 1] BGI-Shenzhen, Shenzhen 518083, China [2] School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China [3]. ; 1] BGI-Shenzhen, Shenzhen 518083, China [2] Binhai Genomics Institute, BGI-Tianjin, Tianjin 300308, China [3] Tianjin Translational Genomics Center, BGI-Tianjin, Tianjin 300308, China [4]. ; 1] The People's Hospital of Lhasa, Lhasa 850000, China [2]. ; Department of Integrative Biology, University of California, Berkeley, California 94720 USA. ; 1] BGI-Shenzhen, Shenzhen 518083, China [2] Binhai Genomics Institute, BGI-Tianjin, Tianjin 300308, China [3] Tianjin Translational Genomics Center, BGI-Tianjin, Tianjin 300308, China. ; 1] BGI-Shenzhen, Shenzhen 518083, China [2] Bioinformatics and Computational Biology Program, Iowa State University, Ames, Iowa 50011, USA. ; Department of Biological Sciences, Middle East Technical University, 06800 Ankara, Turkey. ; BGI-Shenzhen, Shenzhen 518083, China. ; The Second People's Hospital of Tibet Autonomous Region, Lhasa 850000, China. ; The People's Hospital of the Tibet Autonomous Region, Lhasa 850000, China. ; The hospital of XiShuangBanNa Dai Nationalities, Autonomous Jinghong, 666100 Yunnan, China. ; 1] BGI-Shenzhen, Shenzhen 518083, China [2] The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, 518083 Shenzhen, China [3] Shenzhen Key Laboratory of Transomics Biotechnologies, BGI-Shenzhen, 518083 Shenzhen, China. ; 1] BGI-Shenzhen, Shenzhen 518083, China [2] Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia [3] James D. Watson Institute of Genome Science, 310008 Hangzhou, China. ; 1] BGI-Shenzhen, Shenzhen 518083, China [2] James D. Watson Institute of Genome Science, 310008 Hangzhou, China. ; 1] BGI-Shenzhen, Shenzhen 518083, China [2] Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia [3] Department of Biology, University of Copenhagen, Ole MaaloesVej 5, 2200 Copenhagen, Denmark [4] Macau University of Science and Technology, AvenidaWai long, Taipa, Macau 999078, China [5] Department of Medicine, University of Hong Kong 999077, Hong Kong. ; 1] BGI-Shenzhen, Shenzhen 518083, China [2] Department of Integrative Biology, University of California, Berkeley, California 94720 USA [3] Department of Statistics, University of California, Berkeley, California 94720, USA [4] Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043035" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological/*genetics ; *Altitude ; Animals ; Asian Continental Ancestry Group/genetics ; Basic Helix-Loop-Helix Transcription Factors/genetics ; DNA/*genetics ; Gene Frequency ; *Genetic Variation ; Haplotypes ; Hominidae/*genetics ; Humans ; Polymorphism, Single Nucleotide ; Tibet
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  • 4
    Publication Date: 2014-05-03
    Description: The P2Y12 receptor (P2Y12R), one of eight members of the P2YR family expressed in humans, is one of the most prominent clinical drug targets for inhibition of platelet aggregation. Although mutagenesis and modelling studies of the P2Y12R provided useful insights into ligand binding, the agonist and antagonist recognition and function at the P2Y12R remain poorly understood at the molecular level. Here we report the structures of the human P2Y12R in complex with the full agonist 2-methylthio-adenosine-5'-diphosphate (2MeSADP, a close analogue of endogenous agonist ADP) at 2.5 A resolution, and the corresponding ATP derivative 2-methylthio-adenosine-5'-triphosphate (2MeSATP) at 3.1 A resolution. These structures, together with the structure of the P2Y12R with antagonist ethyl 6-(4-((benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283), reveal striking conformational changes between nucleotide and non-nucleotide ligand complexes in the extracellular regions. Further analysis of these changes provides insight into a distinct ligand binding landscape in the delta-group of class A G-protein-coupled receptors (GPCRs). Agonist and non-nucleotide antagonist adopt different orientations in the P2Y12R, with only partially overlapped binding pockets. The agonist-bound P2Y12R structure answers long-standing questions surrounding P2Y12R-agonist recognition, and reveals interactions with several residues that had not been reported to be involved in agonist binding. As a first example, to our knowledge, of a GPCR in which agonist access to the binding pocket requires large-scale rearrangements in the highly malleable extracellular region, the structural and docking studies will therefore provide invaluable insight into the pharmacology and mechanisms of action of agonists and different classes of antagonists for the P2Y12R and potentially for other closely related P2YRs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128917/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128917/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jin -- Zhang, Kaihua -- Gao, Zhan-Guo -- Paoletta, Silvia -- Zhang, Dandan -- Han, Gye Won -- Li, Tingting -- Ma, Limin -- Zhang, Wenru -- Muller, Christa E -- Yang, Huaiyu -- Jiang, Hualiang -- Cherezov, Vadim -- Katritch, Vsevolod -- Jacobson, Kenneth A -- Stevens, Raymond C -- Wu, Beili -- Zhao, Qiang -- R01 AI100604/AI/NIAID NIH HHS/ -- R01AI100604/AI/NIAID NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54GM094618/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2014 May 1;509(7498):119-22. doi: 10.1038/nature13288.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China [2]. ; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. ; PharmaCenter Bonn, University of Bonn, Pharmaceutical Chemistry I, An der Immenburg 4, D-53121 Bonn, Germany. ; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; 1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] iHuman Institute, ShanghaiTech University, 99 Haike Road, Pudong, Shanghai 201203, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24784220" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/*analogs & derivatives/chemistry/metabolism ; Adenosine Triphosphate/*analogs & derivatives/chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Humans ; Ligands ; Models, Molecular ; Niacin/analogs & derivatives/chemistry/metabolism ; Protein Conformation ; Purinergic P2Y Receptor Agonists/*chemistry/metabolism ; Purinergic P2Y Receptor Antagonists/chemistry/metabolism ; Receptors, Purinergic P2Y12/*chemistry/metabolism ; Substrate Specificity ; Sulfonamides/chemistry/metabolism ; Thionucleotides/*chemistry/metabolism
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  • 5
    Publication Date: 2014-03-29
    Description: P2Y receptors (P2YRs), a family of purinergic G-protein-coupled receptors (GPCRs), are activated by extracellular nucleotides. There are a total of eight distinct functional P2YRs expressed in human, which are subdivided into P2Y1-like receptors and P2Y12-like receptors. Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo, which limits our understanding of this receptor family. P2Y12R regulates platelet activation and thrombus formation, and several antithrombotic drugs targeting P2Y12R--including the prodrugs clopidogrel (Plavix) and prasugrel (Effient) that are metabolized and bind covalently, and the nucleoside analogue ticagrelor (Brilinta) that acts directly on the receptor--have been approved for the prevention of stroke and myocardial infarction. However, limitations of these drugs (for example, a very long half-life of clopidogrel action and a characteristic adverse effect profile of ticagrelor) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors. Here we report the 2.6 A resolution crystal structure of human P2Y12R in complex with a non-nucleotide reversible antagonist, AZD1283. The structure reveals a distinct straight conformation of helix V, which sets P2Y12R apart from all other known class A GPCR structures. With AZD1283 bound, the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic. Along with the details of the AZD1283-binding site, analysis of the extracellular interface reveals an adjacent ligand-binding region and suggests that both pockets could be required for dinucleotide binding. The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174307/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174307/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Kaihua -- Zhang, Jin -- Gao, Zhan-Guo -- Zhang, Dandan -- Zhu, Lan -- Han, Gye Won -- Moss, Steven M -- Paoletta, Silvia -- Kiselev, Evgeny -- Lu, Weizhen -- Fenalti, Gustavo -- Zhang, Wenru -- Muller, Christa E -- Yang, Huaiyu -- Jiang, Hualiang -- Cherezov, Vadim -- Katritch, Vsevolod -- Jacobson, Kenneth A -- Stevens, Raymond C -- Wu, Beili -- Zhao, Qiang -- R01 AI100604/AI/NIAID NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- Z99 DK999999/Intramural NIH HHS/ -- ZIA DK031116-26/Intramural NIH HHS/ -- ZIA DK031126-07/Intramural NIH HHS/ -- England -- Nature. 2014 May 1;509(7498):115-8. doi: 10.1038/nature13083. Epub 2014 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China [2]. ; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. ; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, An der Immenburg 4, D-53121 Bonn, Germany. ; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; 1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] iHuman Institute, ShanghaiTech University, 99 Haike Road, Pudong, Shanghai 201203, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670650" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; Disulfides/metabolism ; Fibrinolytic Agents/*chemistry ; Humans ; Ligands ; Models, Molecular ; Molecular Docking Simulation ; Niacin/*analogs & derivatives/chemistry/metabolism ; Protein Conformation ; Purinergic P2Y Receptor Antagonists/chemistry/metabolism ; Receptors, Purinergic P2Y12/*chemistry/metabolism ; Sulfonamides/*chemistry/metabolism
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  • 6
    Publication Date: 2011-03-12
    Description: Activation of G protein-coupled receptors upon agonist binding is a critical step in the signaling cascade for this family of cell surface proteins. We report the crystal structure of the A(2A) adenosine receptor (A(2A)AR) bound to an agonist UK-432097 at 2.7 angstrom resolution. Relative to inactive, antagonist-bound A(2A)AR, the agonist-bound structure displays an outward tilt and rotation of the cytoplasmic half of helix VI, a movement of helix V, and an axial shift of helix III, resembling the changes associated with the active-state opsin structure. Additionally, a seesaw movement of helix VII and a shift of extracellular loop 3 are likely specific to A(2A)AR and its ligand. The results define the molecule UK-432097 as a "conformationally selective agonist" capable of receptor stabilization in a specific active-state configuration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086811/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086811/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Fei -- Wu, Huixian -- Katritch, Vsevolod -- Han, Gye Won -- Jacobson, Kenneth A -- Gao, Zhan-Guo -- Cherezov, Vadim -- Stevens, Raymond C -- GM075915/GM/NIGMS NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- R01 GM089857/GM/NIGMS NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54 GM094618-01/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2011 Apr 15;332(6027):322-7. doi: 10.1126/science.1202793. Epub 2011 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21393508" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine/*analogs & derivatives/chemistry/metabolism ; Adenosine A2 Receptor Agonists/chemistry/*metabolism ; Binding Sites ; Crystallography, X-Ray ; Humans ; Hydrogen Bonding ; Ligands ; Models, Molecular ; Opsins/chemistry/metabolism ; Protein Conformation ; Protein Structure, Secondary ; Receptor, Adenosine A2A/*chemistry/*metabolism ; Rhodopsin/chemistry/metabolism ; Triazines/chemistry/metabolism ; Triazoles/chemistry/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2014-08-29
    Description: The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features. Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a 'universal model' based on a single set of organism-independent parameters.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155737/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155737/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gerstein, Mark B -- Rozowsky, Joel -- Yan, Koon-Kiu -- Wang, Daifeng -- Cheng, Chao -- Brown, James B -- Davis, Carrie A -- Hillier, LaDeana -- Sisu, Cristina -- Li, Jingyi Jessica -- Pei, Baikang -- Harmanci, Arif O -- Duff, Michael O -- Djebali, Sarah -- Alexander, Roger P -- Alver, Burak H -- Auerbach, Raymond -- Bell, Kimberly -- Bickel, Peter J -- Boeck, Max E -- Boley, Nathan P -- Booth, Benjamin W -- Cherbas, Lucy -- Cherbas, Peter -- Di, Chao -- Dobin, Alex -- Drenkow, Jorg -- Ewing, Brent -- Fang, Gang -- Fastuca, Megan -- Feingold, Elise A -- Frankish, Adam -- Gao, Guanjun -- Good, Peter J -- Guigo, Roderic -- Hammonds, Ann -- Harrow, Jen -- Hoskins, Roger A -- Howald, Cedric -- Hu, Long -- Huang, Haiyan -- Hubbard, Tim J P -- Huynh, Chau -- Jha, Sonali -- Kasper, Dionna -- Kato, Masaomi -- Kaufman, Thomas C -- Kitchen, Robert R -- Ladewig, Erik -- Lagarde, Julien -- Lai, Eric -- Leng, Jing -- Lu, Zhi -- MacCoss, Michael -- May, Gemma -- McWhirter, Rebecca -- Merrihew, Gennifer -- Miller, David M -- Mortazavi, Ali -- Murad, Rabi -- Oliver, Brian -- Olson, Sara -- Park, Peter J -- Pazin, Michael J -- Perrimon, Norbert -- Pervouchine, Dmitri -- Reinke, Valerie -- Reymond, Alexandre -- Robinson, Garrett -- Samsonova, Anastasia -- Saunders, Gary I -- Schlesinger, Felix -- Sethi, Anurag -- Slack, Frank J -- Spencer, William C -- Stoiber, Marcus H -- Strasbourger, Pnina -- Tanzer, Andrea -- Thompson, Owen A -- Wan, Kenneth H -- Wang, Guilin -- Wang, Huaien -- Watkins, Kathie L -- Wen, Jiayu -- Wen, Kejia -- Xue, Chenghai -- Yang, Li -- Yip, Kevin -- Zaleski, Chris -- Zhang, Yan -- Zheng, Henry -- Brenner, Steven E -- Graveley, Brenton R -- Celniker, Susan E -- Gingeras, Thomas R -- Waterston, Robert -- 1U01HG007031-01/HG/NHGRI NIH HHS/ -- 5U01HG004695-04/HG/NHGRI NIH HHS/ -- 5U54HG004555/HG/NHGRI NIH HHS/ -- HG007000/HG/NHGRI NIH HHS/ -- HG007355/HG/NHGRI NIH HHS/ -- K99 HG006698/HG/NHGRI NIH HHS/ -- P30 CA045508/CA/NCI NIH HHS/ -- R01 GM076655/GM/NIGMS NIH HHS/ -- RC2-HG005639/HG/NHGRI NIH HHS/ -- T15 LM007056/LM/NLM NIH HHS/ -- T32 HD060555/HD/NICHD NIH HHS/ -- U01 HG 004263/HG/NHGRI NIH HHS/ -- U01 HG004261/HG/NHGRI NIH HHS/ -- U01 HG004271/HG/NHGRI NIH HHS/ -- U01 HG007031/HG/NHGRI NIH HHS/ -- U01-HG004261/HG/NHGRI NIH HHS/ -- U01HG004258/HG/NHGRI NIH HHS/ -- U41 HG007000/HG/NHGRI NIH HHS/ -- U41 HG007234/HG/NHGRI NIH HHS/ -- U41 HG007355/HG/NHGRI NIH HHS/ -- U54 HG004555/HG/NHGRI NIH HHS/ -- U54 HG006944/HG/NHGRI NIH HHS/ -- U54 HG006994/HG/NHGRI NIH HHS/ -- U54 HG007004/HG/NHGRI NIH HHS/ -- U54 HG007005/HG/NHGRI NIH HHS/ -- U54HG007005/HG/NHGRI NIH HHS/ -- WT098051/Wellcome Trust/United Kingdom -- ZIA DK015600-18/Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Aug 28;512(7515):445-8. doi: 10.1038/nature13424.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Program in Computational Biology and Bioinformatics, Yale University, Bass 432, 266 Whitney Avenue, New Haven, Connecticut 06520, USA [2] Department of Molecular Biophysics and Biochemistry, Yale University, Bass 432, 266 Whitney Avenue, New Haven, Connecticut 06520, USA [3] Department of Computer Science, Yale University, 51 Prospect Street, New Haven, Connecticut 06511, USA [4] [5]. ; 1] Program in Computational Biology and Bioinformatics, Yale University, Bass 432, 266 Whitney Avenue, New Haven, Connecticut 06520, USA [2] Department of Molecular Biophysics and Biochemistry, Yale University, Bass 432, 266 Whitney Avenue, New Haven, Connecticut 06520, USA [3]. ; 1] Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA [2] Institute for Quantitative Biomedical Sciences, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03766, USA [3]. ; 1] Department of Genome Dynamics, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA [2] Department of Statistics, University of California, Berkeley, 367 Evans Hall, Berkeley, California 94720-3860, USA [3]. ; 1] Functional Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2]. ; 1] Department of Genome Sciences and University of Washington School of Medicine, William H. Foege Building S350D, 1705 Northeast Pacific Street, Box 355065 Seattle, Washington 98195-5065, USA [2]. ; 1] Department of Statistics, University of California, Berkeley, 367 Evans Hall, Berkeley, California 94720-3860, USA [2] Department of Statistics, University of California, Los Angeles, California 90095-1554, USA [3] Department of Human Genetics, University of California, Los Angeles, California 90095-7088, USA [4]. ; 1] Department of Genetics and Developmental Biology, Institute for Systems Genomics, University of Connecticut Health Center, 400 Farmington Avenue, Farmington, Connecticut 06030, USA [2]. ; 1] Centre for Genomic Regulation, Doctor Aiguader 88, 08003 Barcelona, Catalonia, Spain [2] Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain [3]. ; 1] Program in Computational Biology and Bioinformatics, Yale University, Bass 432, 266 Whitney Avenue, New Haven, Connecticut 06520, USA [2] Department of Molecular Biophysics and Biochemistry, Yale University, Bass 432, 266 Whitney Avenue, New Haven, Connecticut 06520, USA. ; Center for Biomedical Informatics, Harvard Medical School, 10 Shattuck Street, Boston, Massachusetts 02115, USA. ; Functional Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; Department of Statistics, University of California, Berkeley, 367 Evans Hall, Berkeley, California 94720-3860, USA. ; Department of Genome Sciences and University of Washington School of Medicine, William H. Foege Building S350D, 1705 Northeast Pacific Street, Box 355065 Seattle, Washington 98195-5065, USA. ; 1] Department of Genome Dynamics, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA [2] Department of Biostatistics, University of California, Berkeley, 367 Evans Hall, Berkeley, California 94720-3860, USA. ; Department of Genome Dynamics, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. ; 1] Department of Biology, Indiana University, 1001 East 3rd Street, Bloomington, Indiana 47405-7005, USA [2] Center for Genomics and Bioinformatics, Indiana University, 1001 East 3rd Street, Bloomington, Indiana 47405-7005, USA. ; MOE Key Lab of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; National Human Genome Research Institute, National Institutes of Health, 5635 Fishers Lane, Bethesda, Maryland 20892-9307, USA. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; 1] Centre for Genomic Regulation, Doctor Aiguader 88, 08003 Barcelona, Catalonia, Spain [2] Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain. ; 1] Center for Integrative Genomics, University of Lausanne, Genopode building, Lausanne 1015, Switzerland [2] Swiss Institute of Bioinformatics, Genopode building, Lausanne 1015, Switzerland. ; 1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK [2] Medical and Molecular Genetics, King's College London, London WC2R 2LS, UK. ; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520-8005, USA. ; Department of Molecular, Cellular and Developmental Biology, PO Box 208103, Yale University, New Haven, Connecticut 06520, USA. ; Department of Biology, Indiana University, 1001 East 3rd Street, Bloomington, Indiana 47405-7005, USA. ; Sloan-Kettering Institute, 1275 York Avenue, Box 252, New York, New York 10065, USA. ; 1] Department of Genetics and Developmental Biology, Institute for Systems Genomics, University of Connecticut Health Center, 400 Farmington Avenue, Farmington, Connecticut 06030, USA [2] Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213 USA. ; Department of Cell and Developmental Biology, Vanderbilt University, 465 21st Avenue South, Nashville, Tennessee 37232-8240, USA. ; 1] Developmental and Cell Biology, University of California, Irvine, California 92697, USA [2] Center for Complex Biological Systems, University of California, Irvine, California 92697, USA. ; Section of Developmental Genomics, Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Department of Genetics and Developmental Biology, Institute for Systems Genomics, University of Connecticut Health Center, 400 Farmington Avenue, Farmington, Connecticut 06030, USA. ; 1] Department of Genetics and Drosophila RNAi Screening Center, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA [2] Howard Hughes Medical Institute, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. ; Center for Integrative Genomics, University of Lausanne, Genopode building, Lausanne 1015, Switzerland. ; 1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK [2] European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK. ; 1] Bioinformatics and Genomics Programme, Center for Genomic Regulation, Universitat Pompeu Fabra (CRG-UPF), 08003 Barcelona, Catalonia, Spain [2] Institute for Theoretical Chemistry, Theoretical Biochemistry Group (TBI), University of Vienna, Wahringerstrasse 17/3/303, A-1090 Vienna, Austria. ; 1] Department of Genetics and Developmental Biology, Institute for Systems Genomics, University of Connecticut Health Center, 400 Farmington Avenue, Farmington, Connecticut 06030, USA [2] Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; 1] Hong Kong Bioinformatics Centre, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong [2] 5 CUHK-BGI Innovation Institute of Trans-omics, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong. ; 1] Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA [2] Department of Plant and Microbial Biology, University of California, Berkeley, California 94720, USA [3]. ; 1] Department of Genome Dynamics, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25164755" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caenorhabditis elegans/embryology/*genetics/growth & development ; Chromatin/genetics ; Cluster Analysis ; Drosophila melanogaster/*genetics/growth & development ; *Gene Expression Profiling ; Gene Expression Regulation, Developmental/genetics ; Histones/metabolism ; Humans ; Larva/genetics/growth & development ; Models, Genetic ; Molecular Sequence Annotation ; Promoter Regions, Genetic/genetics ; Pupa/genetics/growth & development ; RNA, Untranslated/genetics ; Sequence Analysis, RNA ; Transcriptome/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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