View source for 5uiw


==Crystal Structure of CC Chemokine Receptor 5 (CCR5) in complex with high potency HIV entry inhibitor 5P7-CCL5==
<StructureSection load='5uiw' size='340' side='right'caption='[[5uiw]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5uiw]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridium_pasteurianum Clostridium pasteurianum] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UIW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UIW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.204&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OLA:OLEIC+ACID'>OLA</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</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'>[https://proteopedia.org/fgij/fg.htm?mol=5uiw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uiw OCA], [https://pdbe.org/5uiw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5uiw RCSB], [https://www.ebi.ac.uk/pdbsum/5uiw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5uiw ProSAT]</span></td></tr>
</table>
== Disease ==
[https://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:[https://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 ==
[https://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> [https://www.uniprot.org/uniprot/RUBR_CLOPA RUBR_CLOPA] Rubredoxin is a small nonheme, iron protein lacking acid-labile sulfide. Its single Fe, chelated to 4 Cys, functions as an electron acceptor and may also stabilize the conformation of the molecule.
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== Publication Abstract from PubMed ==
CCR5 is the primary chemokine receptor utilized by HIV to infect leukocytes, whereas CCR5 ligands inhibit infection by blocking CCR5 engagement with HIV gp120. To guide the design of improved therapeutics, we solved the structure of CCR5 in complex with chemokine antagonist [5P7]CCL5. Several structural features appeared to contribute to the anti-HIV potency of [5P7]CCL5, including the distinct chemokine orientation relative to the receptor, the near-complete occupancy of the receptor binding pocket, the dense network of intermolecular hydrogen bonds, and the similarity of binding determinants with the FDA-approved HIV inhibitor Maraviroc. Molecular modeling indicated that HIV gp120 mimicked the chemokine interaction with CCR5, providing an explanation for the ability of CCR5 to recognize diverse ligands and gp120 variants. Our findings reveal that structural plasticity facilitates receptor-chemokine specificity and enables exploitation by HIV, and provide insight into the design of small molecule and protein inhibitors for HIV and other CCR5-mediated diseases.

Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV.,Zheng Y, Han GW, Abagyan R, Wu B, Stevens RC, Cherezov V, Kufareva I, Handel TM Immunity. 2017 Jun 20;46(6):1005-1017.e5. doi: 10.1016/j.immuni.2017.05.002. PMID:28636951<ref>PMID:28636951</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5uiw" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Clostridium pasteurianum]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cherezov V]]
[[Category: Gustavsson M]]
[[Category: Han GW]]
[[Category: Handel TM]]
[[Category: Kawamura T]]
[[Category: Kufareva I]]
[[Category: Qin L]]
[[Category: Stevens RC]]
[[Category: Zheng Y]]