6aky
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | The | + | ==The Crystal structure of Human Chemokine Receptor CCR5 in complex with compound 34== |
| + | <StructureSection load='6aky' size='340' side='right' caption='[[6aky]], [[Resolution|resolution]] 2.80Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6aky]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AKY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6AKY FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A4X:4,4-difluoro-N-[(1S)-3-{(3-exo)-3-[3-methyl-5-(propan-2-yl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}-1-(thiophen-3-yl)propyl]cyclohexane-1-carboxamide'>A4X</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6aky FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6aky OCA], [http://pdbe.org/6aky PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6aky RCSB], [http://www.ebi.ac.uk/pdbsum/6aky PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6aky ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/CCR5_HUMAN CCR5_HUMAN]] Genetic variation in CCR5 is associated with susceptibility to diabetes mellitus insulin-dependent type 22 (IDDM22) [MIM:[http://omim.org/entry/612522 612522]]. A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:19073967</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/CCR5_HUMAN CCR5_HUMAN]] Receptor for a number of inflammatory CC-chemokines including MIP-1-alpha, MIP-1-beta and RANTES and subsequently transduces a signal by increasing the intracellular calcium ion level. May play a role in the control of granulocytic lineage proliferation or differentiation. Acts as a coreceptor (CD4 being the primary receptor) for HIV-1 R5 isolates.<ref>PMID:8639485</ref> <ref>PMID:8663314</ref> <ref>PMID:8699119</ref> <ref>PMID:8649511</ref> <ref>PMID:8649512</ref> <ref>PMID:11323418</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | CC-chemokine receptor 5 (CCR5) is an attractive target for preventing the entry of human immunodeficiency virus 1 (HIV-1) into human host cells. Maraviroc is the only CCR5 antagonist, and it was marketed in 2007. To overcome the shortcomings of maraviroc, structure-based drug design was performed to minimize CYP450 inhibition and to enhance anti-HIV potency and bioavailability. Thirty-four novel 1-heteroaryl-1,3-propanediamine derivatives (1-34) were synthesized, displaying CCR5-antagonist activities in the 2.3-296.4 nM range. Among these, compounds 21 and 34 were the most potent CCR5 antagonists, with excellent in vitro anti-HIV-1 activity, low cytotoxicity, and an acceptable pharmacokinetic profile. Furthermore, the X-ray crystal structures of compounds 21 and 34 bound to CCR5 were determined at 2.8 A resolution. Compound 34 exhibited no CYP450-inhibition activity at 25 muM, which overcomes the potential drug-drug interaction of maraviroc. Compound 34 represents a promising drug candidate for HIV-infection treatment. | ||
| - | + | Structure-Based Design of 1-Heteroaryl-1,3-propanediamine Derivatives as a Novel Series of CC-Chemokine Receptor 5 Antagonists.,Peng P, Chen H, Zhu Y, Wang Z, Li J, Luo RH, Wang J, Chen L, Yang LM, Jiang H, Xie X, Wu B, Zheng YT, Liu H J Med Chem. 2018 Oct 17. doi: 10.1021/acs.jmedchem.8b01077. PMID:30234300<ref>PMID:30234300</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6aky" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Wu, B]] | ||
| + | [[Category: Zhao, Q]] | ||
| + | [[Category: Zhu, Y]] | ||
| + | [[Category: G protein-coupled receptor chemokine receptor ccr5 antagonist complex structure]] | ||
| + | [[Category: Signaling protein]] | ||
Revision as of 05:49, 24 October 2018
The Crystal structure of Human Chemokine Receptor CCR5 in complex with compound 34
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