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Solution structure of FKBP, a rotamase enzyme and receptor for FK506 and rapamycin (1991)

S. W. Michnick ; M. K. Rosen ; T. J. Wandless ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 252(5007): 836-9.

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Publication Date: 1991-05-10

Description: Immunophilins, when complexed to immunosuppressive ligands, appear to inhibit signal transduction pathways that result in exocytosis and transcription. The solution structure of one of these, the human FK506 and rapamycin binding protein (FKBP), has been determined by nuclear magnetic resonance (NMR). FKBP has a previously unobserved antiparallel beta-sheet folding topology that results in a novel loop crossing and produces a large cavity lined by a conserved array of aromatic residues; this cavity serves as the rotamase active site and drug-binding pocket. There are other significant structural features (such as a protruding positively charged loop and an apparently flexible loop) that may be involved in the biological activity of FKBP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Michnick, S W -- Rosen, M K -- Wandless, T J -- Karplus, M -- Schreiber, S L -- GM-30804/GM/NIGMS NIH HHS/ -- GM-38627/GM/NIGMS NIH HHS/ -- I-S10-RR04870/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 1991 May 10;252(5007):836-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Harvard University, Cambridge, MA 02138.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1709301" target="_blank"〉PubMed〈/a〉

Keywords: Anti-Bacterial Agents/metabolism ; Binding Sites ; Carrier Proteins/*ultrastructure ; Crystallography ; Humans ; Immunosuppressive Agents/metabolism ; Magnetic Resonance Spectroscopy ; Molecular Structure ; Polyenes/metabolism ; Sirolimus ; Tacrolimus ; Tacrolimus Binding Proteins

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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Probing immunosuppressant action with a nonnatural immunophilin ligand (1990)

B. E. Bierer ; P. K. Somers ; T. J. Wandless ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 250(4980): 556-9.

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Publication Date: 1990-10-26

Description: The immunosuppressants FK506 and rapamycin bind to the same immunophilin, FK506 binding protein (FKBP), and inhibit distinct signal transduction pathways in T lymphocytes. A nonnatural immunophilin ligand, 506BD, which contains only the common structural elements of FK506 and rapamycin, was synthesized and found to be a high-affinity ligand of FKBP and a potent inhibitor of FKBP rotamase activity. Whereas 506BD does not interfere with T cell activation, it does block the immunosuppressive effects of both FK506 and rapamycin. Thus, the common immunophilin binding element of these immunosuppressants, which is responsible for rotamase inhibition, is fused to different effector elements, resulting in the inhibition of different signaling pathways. Inhibition of rotamase activity is an insufficient requirement for mediating these effects.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bierer, B E -- Somers, P K -- Wandless, T J -- Burakoff, S J -- Schreiber, S L -- GM-38627/GM/NIGMS NIH HHS/ -- P01-CA-39542/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 1990 Oct 26;250(4980):556-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1700475" target="_blank"〉PubMed〈/a〉

Keywords: Anti-Bacterial Agents/antagonists & inhibitors/chemistry/metabolism/*pharmacology ; Antigens, CD3 ; Antigens, Differentiation, T-Lymphocyte/immunology ; Cyclohexanols/chemical synthesis/chemistry/*metabolism/pharmacology ; Hybridomas/immunology ; Immunosuppressive Agents/metabolism/*pharmacology ; Interleukin-2/pharmacology ; Magnetic Resonance Spectroscopy ; Molecular Conformation ; Molecular Structure ; Polyenes/antagonists & inhibitors/chemistry/metabolism/pharmacology ; Pyrans/chemical synthesis/chemistry/*metabolism/pharmacology ; Receptors, Antigen, T-Cell/immunology ; Signal Transduction/drug effects ; Sirolimus ; Solutions ; T-Lymphocytes/drug effects/immunology ; Tacrolimus

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Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

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Controlling signal transduction with synthetic ligands (1993)

D. M. Spencer ; T. J. Wandless ; S. L. Schreiber ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 262(5136): 1019-24.

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Publication Date: 1993-11-12

Description: Dimerization and oligomerization are general biological control mechanisms contributing to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. Cell permeable, synthetic ligands were devised that can be used to control the intracellular oligomerization of specific proteins. To demonstrate their utility, these ligands were used to induce intracellular oligomerization of cell surface receptors that lacked their transmembrane and extracellular regions but contained intracellular signaling domains. Addition of these ligands to cells in culture resulted in signal transmission and specific target gene activation. Monomeric forms of the ligands blocked the pathway. This method of ligand-regulated activation and termination of signaling pathways has the potential to be applied wherever precise control of a signal transduction pathway is desired.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Spencer, D M -- Wandless, T J -- Schreiber, S L -- Crabtree, G R -- New York, N.Y. -- Science. 1993 Nov 12;262(5136):1019-24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Stanford University, CA 94305.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/7694365" target="_blank"〉PubMed〈/a〉

Keywords: Base Sequence ; Carrier Proteins/*metabolism ; Cross-Linking Reagents ; Gene Expression Regulation ; Heat-Shock Proteins/*metabolism ; Ligands ; Membrane Proteins/*metabolism ; Models, Biological ; Molecular Sequence Data ; Polymers ; Receptors, Antigen, T-Cell/*metabolism ; Recombinant Fusion Proteins/metabolism ; *Signal Transduction ; T-Lymphocytes/*metabolism ; Tacrolimus/*analogs & derivatives/chemical synthesis/chemistry/metabolism ; Tacrolimus Binding Proteins ; Transcriptional Activation ; Transfection ; Tumor Cells, Cultured

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Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

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PI(3,4,5)P3 and PI(4,5)P2 lipids target proteins with polybasic clusters to the plasma membrane (2006)

W. D. Heo ; T. Inoue ; W. S. Park ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 314(5804): 1458-61. doi: 10.1126/science.1134389.

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Publication Date: 2006-11-11

Description: Many signaling, cytoskeletal, and transport proteins have to be localized to the plasma membrane (PM) in order to carry out their function. We surveyed PM-targeting mechanisms by imaging the subcellular localization of 125 fluorescent protein-conjugated Ras, Rab, Arf, and Rho proteins. Out of 48 proteins that were PM-localized, 37 contained clusters of positively charged amino acids. To test whether these polybasic clusters bind negatively charged phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] lipids, we developed a chemical phosphatase activation method to deplete PM PI(4,5)P2. Unexpectedly, proteins with polybasic clusters dissociated from the PM only when both PI(4,5)P2 and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] were depleted, arguing that both lipid second messengers jointly regulate PM targeting.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579512/" 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/PMC3579512/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Heo, Won Do -- Inoue, Takanari -- Park, Wei Sun -- Kim, Man Lyang -- Park, Byung Ouk -- Wandless, Thomas J -- Meyer, Tobias -- R01 GM030179/GM/NIGMS NIH HHS/ -- R01 GM030179-24A1/GM/NIGMS NIH HHS/ -- R01 GM030179-25/GM/NIGMS NIH HHS/ -- R01 GM063702/GM/NIGMS NIH HHS/ -- R01 MH064801/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2006 Dec 1;314(5804):1458-61. Epub 2006 Nov 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Pharmacology, 318 Campus Drive, Clark Building, Stanford University Medical School, Stanford, CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17095657" target="_blank"〉PubMed〈/a〉

Keywords: ADP-Ribosylation Factors/chemistry/metabolism ; Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Cell Membrane/*metabolism ; GTP Phosphohydrolases/chemistry/*metabolism ; HeLa Cells ; Humans ; Hydrophobic and Hydrophilic Interactions ; Kinetics ; Mice ; Molecular Sequence Data ; NIH 3T3 Cells ; Phosphatidylinositol 4,5-Diphosphate/*metabolism ; Phosphatidylinositol Phosphates/*metabolism ; Second Messenger Systems ; Signal Transduction ; Static Electricity ; rab GTP-Binding Proteins/chemistry/metabolism ; ras Proteins/chemistry/metabolism ; rho GTP-Binding Proteins/metabolism

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Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

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A plant-like kinase in Plasmodium falciparum regulates parasite egress from erythrocytes (2010)

J. D. Dvorin ; D. C. Martyn ; S. D. Patel ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 328(5980): 910-2. doi: 10.1126/science.1188191.

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Publication Date: 2010-05-15

Description: Clinical malaria is associated with the proliferation of Plasmodium parasites in human erythrocytes. The coordinated processes of parasite egress from and invasion into erythrocytes are rapid and tightly regulated. We have found that the plant-like calcium-dependent protein kinase PfCDPK5, which is expressed in invasive merozoite forms of Plasmodium falciparum, was critical for egress. Parasites deficient in PfCDPK5 arrested as mature schizonts with intact membranes, despite normal maturation of egress proteases and invasion ligands. Merozoites physically released from stalled schizonts were capable of invading new erythrocytes, separating the pathways of egress and invasion. The arrest was downstream of cyclic guanosine monophosphate-dependent protein kinase (PfPKG) function and independent of protease processing. Thus, PfCDPK5 plays an essential role during the blood stage of malaria replication.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109083/" 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/PMC3109083/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dvorin, Jeffrey D -- Martyn, Derek C -- Patel, Saurabh D -- Grimley, Joshua S -- Collins, Christine R -- Hopp, Christine S -- Bright, A Taylor -- Westenberger, Scott -- Winzeler, Elizabeth -- Blackman, Michael J -- Baker, David A -- Wandless, Thomas J -- Duraisingh, Manoj T -- 086550/Wellcome Trust/United Kingdom -- G1000779/Medical Research Council/United Kingdom -- GM073046/GM/NIGMS NIH HHS/ -- K08 AI087874/AI/NIAID NIH HHS/ -- K12-HD000850/HD/NICHD NIH HHS/ -- MC_U117532063/Medical Research Council/United Kingdom -- R01 AI057919/AI/NIAID NIH HHS/ -- R01 AI057919-05/AI/NIAID NIH HHS/ -- R01 GM073046/GM/NIGMS NIH HHS/ -- R01AI057919/AI/NIAID NIH HHS/ -- U117532063/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2010 May 14;328(5980):910-2. doi: 10.1126/science.1188191.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20466936" target="_blank"〉PubMed〈/a〉

Keywords: Calcium-Binding Proteins/chemistry/genetics/*metabolism ; Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors/metabolism ; Enzyme Inhibitors/pharmacology ; Erythrocytes/*parasitology ; Host-Parasite Interactions ; Humans ; Ligands ; Merozoites/enzymology/physiology ; Models, Biological ; Morpholines/metabolism ; Plasmodium falciparum/cytology/enzymology/growth & development/*physiology ; Protein Kinases/chemistry/genetics/*metabolism ; Protozoan Proteins/chemistry/genetics/*metabolism ; Pyridines/pharmacology ; Pyrroles/pharmacology ; Recombinant Fusion Proteins/chemistry/metabolism ; Schizonts/cytology/enzymology/physiology

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Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

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