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| | <StructureSection load='5t1a' size='340' side='right'caption='[[5t1a]], [[Resolution|resolution]] 2.81Å' scene=''> | | <StructureSection load='5t1a' size='340' side='right'caption='[[5t1a]], [[Resolution|resolution]] 2.81Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5t1a]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T1A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5T1A FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5t1a]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_virus_T4 Escherichia virus T4] 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=5T1A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5T1A FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=73R:(3S)-1-{(1S,2R,4R)-4-[METHYL(PROPAN-2-YL)AMINO]-2-PROPYLCYCLOHEXYL}-3-{[6-(TRIFLUOROMETHYL)QUINAZOLIN-4-YL]AMINO}PYRROLIDIN-2-ONE'>73R</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=VT5:(2~{R})-1-(4-CHLORANYL-2-FLUORANYL-PHENYL)-2-CYCLOHEXYL-3-ETHANOYL-4-OXIDANYL-2~{H}-PYRROL-5-ONE'>VT5</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.806Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=73R:(3S)-1-{(1S,2R,4R)-4-[METHYL(PROPAN-2-YL)AMINO]-2-PROPYLCYCLOHEXYL}-3-{[6-(TRIFLUOROMETHYL)QUINAZOLIN-4-YL]AMINO}PYRROLIDIN-2-ONE'>73R</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=VT5:(2~{R})-1-(4-CHLORANYL-2-FLUORANYL-PHENYL)-2-CYCLOHEXYL-3-ETHANOYL-4-OXIDANYL-2~{H}-PYRROL-5-ONE'>VT5</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</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">e, T4Tp126 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5t1a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t1a OCA], [https://pdbe.org/5t1a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5t1a RCSB], [https://www.ebi.ac.uk/pdbsum/5t1a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5t1a ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Lysozyme Lysozyme], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.17 3.2.1.17] </span></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=5t1a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t1a OCA], [http://pdbe.org/5t1a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t1a RCSB], [http://www.ebi.ac.uk/pdbsum/5t1a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t1a ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CCR2_HUMAN CCR2_HUMAN]] Receptor for the CCL2, CCL7 and CCL13 chemokines. Transduces a signal by increasing intracellular calcium ion levels. Alternative coreceptor with CD4 for HIV-1 infection.<ref>PMID:23408426</ref> | + | [https://www.uniprot.org/uniprot/ENLYS_BPT4 ENLYS_BPT4] Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.<ref>PMID:22389108</ref> [https://www.uniprot.org/uniprot/CCR2_HUMAN CCR2_HUMAN] Receptor for the CCL2, CCL7 and CCL13 chemokines. Transduces a signal by increasing intracellular calcium ion levels. Alternative coreceptor with CD4 for HIV-1 infection.<ref>PMID:23408426</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Escherichia virus T4]] |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lysozyme]]
| + | [[Category: Abagyan R]] |
| - | [[Category: Abagyan, R]] | + | [[Category: Carter P]] |
| - | [[Category: Carter, P]] | + | [[Category: Cherezov V]] |
| - | [[Category: Cherezov, V]] | + | [[Category: Cherney RJ]] |
| - | [[Category: Cherney, R J]] | + | [[Category: Dabros M]] |
| - | [[Category: Dabros, M]] | + | [[Category: Gustavsson M]] |
| - | [[Category: Gustavsson, M]] | + | [[Category: Han GW]] |
| - | [[Category: Han, G W]] | + | [[Category: Handel TM]] |
| - | [[Category: Handel, T M]] | + | [[Category: Heitman LH]] |
| - | [[Category: Heitman, L H]] | + | [[Category: IJzerman AP]] |
| - | [[Category: IJzerman, A P]] | + | [[Category: Kufareva I]] |
| - | [[Category: Kufareva, I]] | + | [[Category: Ortiz Zacarias NV]] |
| - | [[Category: Qin, L]] | + | [[Category: Qin L]] |
| - | [[Category: Stamos, D]] | + | [[Category: Stamos D]] |
| - | [[Category: Stevens, R C]] | + | [[Category: Stevens RC]] |
| - | [[Category: Tebben, A]] | + | [[Category: Tebben A]] |
| - | [[Category: Vries, H de]]
| + | [[Category: Zhao C]] |
| - | [[Category: Zacarias, N V.Ortiz]]
| + | [[Category: Zheng Y]] |
| - | [[Category: Zhao, C]] | + | [[Category: De Vries H]] |
| - | [[Category: Zheng, Y]] | + | |
| - | [[Category: C-c chemokine receptor type 2]] | + | |
| - | [[Category: Cooperative binding]]
| + | |
| - | [[Category: Dual antagonist]]
| + | |
| - | [[Category: Gpcr]]
| + | |
| - | [[Category: Gpcr network]]
| + | |
| - | [[Category: Intracellular allosteric antagonist]]
| + | |
| - | [[Category: Lipidic cubic phase]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: PSI, Protein structure initiative]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Structural genomic]]
| + | |
| Structural highlights
5t1a is a 1 chain structure with sequence from Escherichia virus T4 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.806Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
ENLYS_BPT4 Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.[1] CCR2_HUMAN Receptor for the CCL2, CCL7 and CCL13 chemokines. Transduces a signal by increasing intracellular calcium ion levels. Alternative coreceptor with CD4 for HIV-1 infection.[2]
Publication Abstract from PubMed
CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer. These disease associations have motivated numerous preclinical studies and clinical trials (see http://www.clinicaltrials.gov) in search of therapies that target the CCR2-chemokine axis. To aid drug discovery efforts, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein-protein interactions, receptor-chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.
Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists.,Zheng Y, Qin L, Zacarias NV, de Vries H, Han GW, Gustavsson M, Dabros M, Zhao C, Cherney RJ, Carter P, Stamos D, Abagyan R, Cherezov V, Stevens RC, IJzerman AP, Heitman LH, Tebben A, Kufareva I, Handel TM Nature. 2016 Dec 7. doi: 10.1038/nature20605. PMID:27926736[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Moussa SH, Kuznetsov V, Tran TA, Sacchettini JC, Young R. Protein determinants of phage T4 lysis inhibition. Protein Sci. 2012 Apr;21(4):571-82. doi: 10.1002/pro.2042. Epub 2012 Mar 2. PMID:22389108 doi:http://dx.doi.org/10.1002/pro.2042
- ↑ Tan JH, Ludeman JP, Wedderburn J, Canals M, Hall P, Butler SJ, Taleski D, Christopoulos A, Hickey MJ, Payne RJ, Stone MJ. Tyrosine sulfation of chemokine receptor CCR2 enhances interactions with both monomeric and dimeric forms of the chemokine monocyte chemoattractant protein-1 (MCP-1). J Biol Chem. 2013 Apr 5;288(14):10024-34. doi: 10.1074/jbc.M112.447359. Epub 2013, Feb 13. PMID:23408426 doi:http://dx.doi.org/10.1074/jbc.M112.447359
- ↑ Zheng Y, Qin L, Zacarias NV, de Vries H, Han GW, Gustavsson M, Dabros M, Zhao C, Cherney RJ, Carter P, Stamos D, Abagyan R, Cherezov V, Stevens RC, IJzerman AP, Heitman LH, Tebben A, Kufareva I, Handel TM. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature. 2016 Dec 7. doi: 10.1038/nature20605. PMID:27926736 doi:http://dx.doi.org/10.1038/nature20605
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