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  • 1
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    Caspase-1 causes {alpha}-synuclein aggregation [Medical Sciences] (2016)
    National Academy of Sciences
    Details
    Publication Date: 2016-08-24
    Description: The aggregation of α-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson’s disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Convergent solutions to binding at a protein-protein interface (2000)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2000-02-26
    Description: The hinge region on the Fc fragment of human immunoglobulin G interacts with at least four different natural protein scaffolds that bind at a common site between the C(H2) and C(H3) domains. This "consensus" site was also dominant for binding of random peptides selected in vitro for high affinity (dissociation constant, about 25 nanomolar) by bacteriophage display. Thus, this site appears to be preferred owing to its intrinsic physiochemical properties, and not for biological function alone. A 2.7 angstrom crystal structure of a selected 13-amino acid peptide in complex with Fc demonstrated that the peptide adopts a compact structure radically different from that of the other Fc binding proteins. Nevertheless, the specific Fc binding interactions of the peptide strongly mimic those of the other proteins. Juxtaposition of the available Fc-complex crystal structures showed that the convergent binding surface is highly accessible, adaptive, and hydrophobic and contains relatively few sites for polar interactions. These are all properties that may promote cross-reactive binding, which is common to protein-protein interactions and especially hormone-receptor complexes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DeLano, W L -- Ultsch, M H -- de Vos, A M -- Wells, J A -- New York, N.Y. -- Science. 2000 Feb 18;287(5456):1279-83.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Graduate Group in Biophysics, University of California, San Francisco, CA 94143, USA and Sunesis Pharmaceuticals, 3696 Haven Avenue, Suite C, Redwood City, CA 94063, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10678837" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acid Substitution ; Binding Sites, Antibody ; Crystallography, X-Ray ; Dimerization ; Evolution, Molecular ; Humans ; Hydrogen Bonding ; Immunoglobulin Fc Fragments/chemistry/*metabolism ; Immunoglobulin G/chemistry/*metabolism ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Peptide Library ; Peptides/chemistry/*metabolism ; Protein Binding ; Protein Conformation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, Fc/chemistry/metabolism ; Rheumatoid Factor/chemistry/metabolism ; Staphylococcal Protein A/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    Repairing research integrity (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-06-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Titus, Sandra L -- Wells, James A -- Rhoades, Lawrence J -- England -- Nature. 2008 Jun 19;453(7198):980-2. doi: 10.1038/453980a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Office of Research Integrity, 1101 Wootton Parkway, Suite 750, Rockville, Maryland 20852, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18563131" target="_blank"〉PubMed〈/a〉
    Keywords: Ethics, Research/*education ; Guidelines as Topic ; Mentors/education ; Reproducibility of Results ; Research Personnel/education/*ethics/psychology/standards ; Scientific Misconduct/legislation & jurisprudence/psychology/*statistics & ; numerical data ; Surveys and Questionnaires ; Whistleblowing/legislation & jurisprudence/psychology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    Zinc mediation of the binding of human growth hormone to the human prolactin receptor (1990)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1990-12-21
    Description: Human growth hormone (hGH) elicits a diverse set of biological activities including lactation that derives from binding to the prolactin (PRL) receptor. The binding affinity of hGH for the extracellular binding domain of the hPRL receptor (hPRLbp) was increased about 8000-fold by addition of 50 micromolar ZnCl2. Zinc was not required for binding of hGH to the hGH binding protein (hGHbp) or for binding of hPRL to the hPRLbp. Other divalent metal ions (Ca2+, Mg2+, Cu2+, Mn2+, and Co2+) at physiological concentrations did not support such strong binding. Scatchard analysis indicated a stoichiometry of one Zn2+ per hGH.hPRLbp complex. Mutational analysis showed that a cluster of three residues (His18, His21, and Glu174) in hGH and His188 from the hPRLbp (conserved in all PRL receptors but not GH receptors) are probable Zn2+ ligands. This polypeptide hormone.receptor "zinc sandwich" provides a molecular mechanism to explain why nonprimate GHs are not lactogenic and offers a molecular link between zinc deficiency and its association with altered functions of hGH.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cunningham, B C -- Bass, S -- Fuh, G -- Wells, J A -- New York, N.Y. -- Science. 1990 Dec 21;250(4988):1709-12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Protein Engineering, Genentech, Inc., South San Francisco, CA 94080.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/2270485" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Base Sequence ; Binding Sites ; Chlorides/*pharmacology ; Growth Hormone/*metabolism ; Humans ; Kinetics ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Oligonucleotide Probes ; Plasmids ; Protein Conformation ; Receptors, Prolactin/drug effects/genetics/*metabolism ; Restriction Mapping ; Zinc/metabolism/*pharmacology ; *Zinc Compounds
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 5
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    Dimerization of human growth hormone by zinc (1991)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1991-08-02
    Description: Size-exclusion chromatography and sedimentation equilbrium studies demonstrated that zinc ion (Zn2+) induced the dimerization of human growth hormone (hGH). Scatchard analysis of 65Zn2+ binding to hGH showed that two Zn2+ ions associate per dimer of hGH in a cooperative fashion. Cobalt (II) can substitute for Zn2+ in the hormone dimer and gives a visible spectrum characteristic of cobalt coordinated in a tetrahedral fashion by oxygen- and nitrogen-containing ligands. Replacement of potential Zn2+ ligands (His18, His21, and Glu174) in hGH with alanine weakened both Zn2+ binding and hGH dimer formation. The Zn(2+)-hGH dimer was more stable than monomeric hGH to denaturation in guanidine-HCl. Formation of a Zn(2+)-hGH dimeric complex may be important for storage of hGH in secretory granules.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cunningham, B C -- Mulkerrin, M G -- Wells, J A -- New York, N.Y. -- Science. 1991 Aug 2;253(5019):545-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Protein Engineering, Genentech, South San Francisco, CA 94080.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1907025" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding Sites ; Chromatography, Gel ; Edetic Acid/pharmacology ; Growth Hormone/*metabolism ; Humans ; Kinetics ; Macromolecular Substances ; Models, Molecular ; Protein Binding ; Protein Conformation ; Protein Denaturation ; Spectrophotometry ; Zinc/metabolism/*pharmacology
    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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  • 6
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    Engineering human prolactin to bind to the human growth hormone receptor (1990)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1990-03-23
    Description: A strategy of iterative site-directed mutagenesis and binding analysis was used to incorporate the receptor-binding determinants from human growth hormone (hGH) into the nonbinding homolog, human prolactin (hPRL). The complementary DNA for hPRL was cloned, expressed in Escherichia coli, and mutated to introduce sequentially those substitutions from hGH that were predicted by alanine-scanning mutagenesis and other studies to be most critical for binding to the hGH receptor from human liver. After seven rounds of site-specific mutagenesis, a variant of hPRL was obtained containing eight mutations with an association constant for the hGH receptor that was increased more than 10,000-fold. This hPRL variant binds one-sixth as strongly as wild-type hGH, but shares only 26 percent overall sequence identity with hGH. These studies show the feasibility of recruiting receptor-binding properties from distantly related and functionally divergent hormones and show that a detailed functional database can be used to guide the design of a protein-protein interface in the absence of direct structural information.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cunningham, B C -- Henner, D J -- Wells, J A -- New York, N.Y. -- Science. 1990 Mar 23;247(4949 Pt 1):1461-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Protein Engineering, Genentech, Inc. South San Francisco, CA 94080.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/2321008" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Base Sequence ; Cloning, Molecular ; Growth Hormone/genetics ; Humans ; Molecular Sequence Data ; Mutation ; Plasmids ; Prolactin/genetics/*metabolism ; Protein Conformation ; Receptors, Somatotropin/*metabolism ; Recombinant Proteins/metabolism
    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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  • 7
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    Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule (1991)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1991-11-08
    Description: Human growth hormone (hGH) forms a 1:2 complex with the extracellular domain of its receptor-binding protein (hGHbp) as studied by crystallization, size exclusion chromatography, calorimetry, and a previously undescribed fluorescence quenching assay. These and other experiments with protein engineered variants of hGH have led to the identification of the binding determinants for two distinct but adjacent sites on hGH for the hGHbp, and the data indicated that there are two overlapping binding sites on the hGHbp for hGH. Furthermore, the binding of hGH to the hGHbp occurred sequentially; a first hGHbp molecule bound to site 1 on hGH and then a second hGHbp bound to site 2. Hormone-induced receptor dimerization is proposed to be relevant to the signal transduction mechanism for the hGH receptor and other related cytokine receptors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cunningham, B C -- Ultsch, M -- De Vos, A M -- Mulkerrin, M G -- Clauser, K R -- Wells, J A -- New York, N.Y. -- Science. 1991 Nov 8;254(5033):821-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Protein Engineering, Genentech, Inc., South San Francisco, CA 94080.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1948064" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Antibodies, Monoclonal ; Binding Sites ; Chromatography, Gel ; Growth Hormone/*metabolism ; Humans ; Kinetics ; Macromolecular Substances ; Models, Structural ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Protein Conformation ; Receptors, Somatotropin/genetics/isolation & purification/*metabolism
    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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  • 8
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    Small-molecule activators of a proenzyme (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-11-07
    Description: Virtually all of the 560 human proteases are stored as inactive proenyzmes and are strictly regulated. We report the identification and characterization of the first small molecules that directly activate proenzymes, the apoptotic procaspases-3 and -6. It is surprising that these compounds induce autoproteolytic activation by stabilizing a conformation that is both more active and more susceptible to intermolecular proteolysis. These procaspase activators bypass the normal upstream proapoptotic signaling cascades and induce rapid apoptosis in a variety of cell lines. Systematic biochemical and biophysical analyses identified a cluster of mutations in procaspase-3 that resist small-molecule activation both in vitro and in cells. Compounds that induce gain of function are rare, and the activators reported here will enable direct control of the executioner caspases in apoptosis and in cellular differentiation. More generally, these studies presage the discovery of other proenzyme activators to explore fundamental processes of proenzyme activation and their fate-determining roles in biology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886848/" 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/PMC2886848/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wolan, Dennis W -- Zorn, Julie A -- Gray, Daniel C -- Wells, James A -- F32 CA119641/CA/NCI NIH HHS/ -- F32 CA119641-03/CA/NCI NIH HHS/ -- R01 CA136779/CA/NCI NIH HHS/ -- R21 N5057022/PHS HHS/ -- New York, N.Y. -- Science. 2009 Nov 6;326(5954):853-8. doi: 10.1126/science.1177585.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmaceutical Chemistry, University of California, San Francisco, Byers Hall, 1700 4th Street, San Francisco, CA 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19892984" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis ; Benzopyrans/chemistry/*metabolism/pharmacology ; Biocatalysis ; Caspase 3/chemistry/genetics/*metabolism ; Caspase 6/chemistry/genetics/*metabolism ; Caspase Inhibitors ; Catalytic Domain ; Cell Line, Transformed ; Cell Line, Tumor ; Cells, Cultured ; Enzyme Activation ; Enzyme Activators/chemistry/*metabolism/pharmacology ; Enzyme Inhibitors/metabolism/pharmacology ; Enzyme Precursors/antagonists & inhibitors/chemistry/genetics/*metabolism ; Granzymes/metabolism ; Humans ; Imidazoles/chemistry/*metabolism/pharmacology ; Kinetics ; Mice ; Molecular Structure ; Mutagenesis ; Pyridines/chemistry/*metabolism/pharmacology ; Signal Transduction ; Small Molecule Libraries/chemistry/metabolism
    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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  • 9
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    Structural plasticity in a remodeled protein-protein interface (1997)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1997-11-14
    Description: Remodeling of the interface between human growth hormone (hGH) and the extracellular domain of its receptor was studied by deleting a critical tryptophan residue (at position 104) in the receptor, creating a large cavity, and selecting a pentamutant of hGH by phage display that fills the cavity and largely restores binding affinity. A 2.1 A resolution x-ray structure of the mutant complex showed that the receptor cavity was filled by selected hydrophobic mutations of hGH. Large structural rearrangements occurred in the interface at sites that were distant from the mutations. Such plasticity may be a means for protein-protein interfaces to adapt to mutations as they coevolve.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Atwell, S -- Ultsch, M -- De Vos, A M -- Wells, J A -- New York, N.Y. -- Science. 1997 Nov 7;278(5340):1125-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Protein Engineering, Genentech, Incorporated, 460 Point San Bruno Boulevard, South San Francisco, CA 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9353194" target="_blank"〉PubMed〈/a〉
    Keywords: Carrier Proteins/*chemistry/genetics/*metabolism ; Crystallography, X-Ray ; Human Growth Hormone/*chemistry/genetics/*metabolism ; Humans ; Hydrogen Bonding ; Models, Molecular ; Mutagenesis ; Peptide Library ; Protein Binding ; *Protein Conformation
    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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  • 10
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    K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-11-22
    Description: Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Efforts to target this oncogene directly have faced difficulties owing to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent on relative nucleotide affinity and concentration. This gives GTP an advantage over GDP and increases the proportion of active GTP-bound Ras. Here we report the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras(G12C). These compounds rely on the mutant cysteine for binding and therefore do not affect the wild-type protein. Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras(G12C) disrupts both switch-I and switch-II, subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274051/" 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/PMC4274051/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ostrem, Jonathan M -- Peters, Ulf -- Sos, Martin L -- Wells, James A -- Shokat, Kevan M -- T32 GM064337/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 28;503(7477):548-51. doi: 10.1038/nature12796. Epub 2013 Nov 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24256730" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/drug effects ; Allosteric Site/*drug effects ; Apoptosis/drug effects ; Cell Line, Tumor ; Crystallography, X-Ray ; Cysteine/genetics/metabolism ; Drug Discovery ; Genes, ras/genetics ; Guanosine Diphosphate/*metabolism ; Guanosine Triphosphate/*metabolism ; Humans ; Lung Neoplasms/drug therapy/metabolism/pathology ; Models, Molecular ; Mutant Proteins/*antagonists & inhibitors/genetics/*metabolism ; Oncogene Protein p21(ras)/*antagonists & inhibitors/genetics/*metabolism ; Static Electricity ; Substrate Specificity ; raf Kinases/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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