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{{STRUCTURE_4mbs|  PDB=4mbs  |  SCENE=  }}
===Crystal Structure of the CCR5 Chemokine Receptor===
{{ABSTRACT_PUBMED_24030490}}


==Disease==
==Crystal Structure of the CCR5 Chemokine Receptor==
<StructureSection load='4mbs' size='340' side='right' caption='[[4mbs]], [[Resolution|resolution]] 2.71&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4mbs]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_pasteurianus"_(winogradsky_1895)_lehmann_and_neumann_1907 "bacillus pasteurianus" (winogradsky 1895) lehmann and neumann 1907]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MBS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MBS FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MRV: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]OCT-8-YL}-1-PHENYLPROPYL]CYCLOHEXANECARBOXAMIDE'>MRV</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CCR5, CCR5_HUMAN, CMKBR5, Rd ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1501 "Bacillus pasteurianus" (Winogradsky 1895) Lehmann and Neumann 1907])</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=4mbs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mbs OCA], [http://pdbe.org/4mbs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4mbs RCSB], [http://www.ebi.ac.uk/pdbsum/4mbs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4mbs 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>   
[[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 ==
==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>   
[[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 ==
The CCR5 chemokine receptor acts as a co-receptor for HIV-1 viral entry. Here we report the 2.7 angstrom-resolution crystal structure of human CCR5 bound to the marketed HIV drug maraviroc. The structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 crystal structures, along with models of co-receptor-gp120-V3 complexes, suggests that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 co-receptor selectivity. These high-resolution insights into CCR5 can enable structure-based drug discovery for the treatment of HIV-1 infection.


==About this Structure==
Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex.,Tan Q, Zhu Y, Li J, Chen Z, Han GW, Kufareva I, Li T, Ma L, Fenalti G, Li J, Zhang W, Xie X, Yang H, Jiang H, Cherezov V, Liu H, Stevens RC, Zhao Q, Wu B Science. 2013 Sep 20;341(6152):1387-90. doi: 10.1126/science.1241475. Epub 2013, Sep 12. PMID:24030490<ref>PMID:24030490</ref>
[[4mbs]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MBS OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
<ref group="xtra">PMID:024030490</ref><references group="xtra"/><references/>
</div>
[[Category: Cherezov, V.]]
<div class="pdbe-citations 4mbs" style="background-color:#fffaf0;"></div>
[[Category: Fenalti, G.]]
== References ==
[[Category: GPCR, GPCR Network.]]
<references/>
[[Category: Han, G W.]]
__TOC__
[[Category: Li, J.]]
</StructureSection>
[[Category: Liu, H.]]
[[Category: Cherezov, V]]
[[Category: Stevens, R C.]]
[[Category: Fenalti, G]]
[[Category: Tan, Q.]]
[[Category: GPCR, GPCR Network]]
[[Category: Wu, B.]]
[[Category: Han, G W]]
[[Category: Zhao, Q.]]
[[Category: Li, J]]
[[Category: Zhu, Y.]]
[[Category: Liu, H]]
[[Category: Stevens, R C]]
[[Category: Tan, Q]]
[[Category: Wu, B]]
[[Category: Zhao, Q]]
[[Category: Zhu, Y]]
[[Category: Anti-hiv agent]]
[[Category: Anti-hiv agent]]
[[Category: G protein-coupled receptor]]
[[Category: G protein-coupled receptor]]

Revision as of 16:10, 4 August 2016

Crystal Structure of the CCR5 Chemokine ReceptorCrystal Structure of the CCR5 Chemokine Receptor

Structural highlights

4mbs is a 2 chain structure with sequence from "bacillus_pasteurianus"_(winogradsky_1895)_lehmann_and_neumann_1907 "bacillus pasteurianus" (winogradsky 1895) lehmann and neumann 1907. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, ,
Gene:CCR5, CCR5_HUMAN, CMKBR5, Rd ("Bacillus pasteurianus" (Winogradsky 1895) Lehmann and Neumann 1907)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CCR5_HUMAN] Genetic variation in CCR5 is associated with susceptibility to diabetes mellitus insulin-dependent type 22 (IDDM22) [MIM: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.[1]

Function

[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.[2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

The CCR5 chemokine receptor acts as a co-receptor for HIV-1 viral entry. Here we report the 2.7 angstrom-resolution crystal structure of human CCR5 bound to the marketed HIV drug maraviroc. The structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 crystal structures, along with models of co-receptor-gp120-V3 complexes, suggests that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 co-receptor selectivity. These high-resolution insights into CCR5 can enable structure-based drug discovery for the treatment of HIV-1 infection.

Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex.,Tan Q, Zhu Y, Li J, Chen Z, Han GW, Kufareva I, Li T, Ma L, Fenalti G, Li J, Zhang W, Xie X, Yang H, Jiang H, Cherezov V, Liu H, Stevens RC, Zhao Q, Wu B Science. 2013 Sep 20;341(6152):1387-90. doi: 10.1126/science.1241475. Epub 2013, Sep 12. PMID:24030490[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JH, Howson JM, Stevens H, McManus R, Wijmenga C, Heap GA, Dubois PC, Clayton DG, Hunt KA, van Heel DA, Todd JA. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med. 2008 Dec 25;359(26):2767-77. doi: 10.1056/NEJMoa0807917. Epub 2008 , Dec 10. PMID:19073967 doi:10.1056/NEJMoa0807917
  2. ↑ Samson M, Labbe O, Mollereau C, Vassart G, Parmentier M. Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry. 1996 Mar 19;35(11):3362-7. PMID:8639485 doi:10.1021/bi952950g
  3. ↑ Raport CJ, Gosling J, Schweickart VL, Gray PW, Charo IF. Molecular cloning and functional characterization of a novel human CC chemokine receptor (CCR5) for RANTES, MIP-1beta, and MIP-1alpha. J Biol Chem. 1996 Jul 19;271(29):17161-6. PMID:8663314
  4. ↑ Combadiere C, Ahuja SK, Tiffany HL, Murphy PM. Cloning and functional expression of CC CKR5, a human monocyte CC chemokine receptor selective for MIP-1(alpha), MIP-1(beta), and RANTES. J Leukoc Biol. 1996 Jul;60(1):147-52. PMID:8699119
  5. ↑ Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996 Jun 20;381(6584):661-6. PMID:8649511 doi:10.1038/381661a0
  6. ↑ Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, Cayanan C, Maddon PJ, Koup RA, Moore JP, Paxton WA. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature. 1996 Jun 20;381(6584):667-73. PMID:8649512 doi:10.1038/381667a0
  7. ↑ Blanpain C, Wittamer V, Vanderwinden JM, Boom A, Renneboog B, Lee B, Le Poul E, El Asmar L, Govaerts C, Vassart G, Doms RW, Parmentier M. Palmitoylation of CCR5 is critical for receptor trafficking and efficient activation of intracellular signaling pathways. J Biol Chem. 2001 Jun 29;276(26):23795-804. Epub 2001 Apr 25. PMID:11323418 doi:10.1074/jbc.M100583200
  8. ↑ Tan Q, Zhu Y, Li J, Chen Z, Han GW, Kufareva I, Li T, Ma L, Fenalti G, Li J, Zhang W, Xie X, Yang H, Jiang H, Cherezov V, Liu H, Stevens RC, Zhao Q, Wu B. Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science. 2013 Sep 20;341(6152):1387-90. doi: 10.1126/science.1241475. Epub 2013, Sep 12. PMID:24030490 doi:10.1126/science.1241475

4mbs, resolution 2.71Å

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