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New page: '''Unreleased structure''' The entry 6zdv is ON HOLD Authors: Verdon, G., Jespers, W., Azuaje, J., Majellaro, M., Keranen, H., Garcia-mera, X., Congreve, M., Deflorian, F., de Graaf, C.... |
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==Crystal structure of stabilized A2A adenosine receptor A2AR-StaR2-bRIL in complex with Chromone 5d== | |||
<StructureSection load='6zdv' size='340' side='right'caption='[[6zdv]], [[Resolution|resolution]] 2.13Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZDV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZDV 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]] 2.13Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=OLA:OLEIC+ACID'>OLA</scene>, <scene name='pdbligand=OLB:(2S)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLB</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=QGW:[2-methyl-3-(4-methyl-1,3-thiazol-2-yl)-4-oxidanylidene-6-propyl-chromen-7-yl]+ethanoate'>QGW</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=6zdv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zdv OCA], [https://pdbe.org/6zdv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zdv RCSB], [https://www.ebi.ac.uk/pdbsum/6zdv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zdv ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X-ray crystallography to reveal the binding mode of an antagonist series to the A2A adenosine receptor (AR). Eight A2A AR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A2A AR were experimentally determined and investigated through a cycle of ligand-FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X-ray crystallography of the A2A AR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A2A AR, an emerging target in immuno-oncology. | |||
X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists.,Jespers W, Verdon G, Azuaje J, Majellaro M, Keranen H, Garcia-Mera X, Congreve M, Deflorian F, de Graaf C, Zhukov A, Dore AS, Mason JS, Aqvist J, Cooke RM, Sotelo E, Gutierrez-de-Teran H Angew Chem Int Ed Engl. 2020 Jun 16. doi: 10.1002/anie.202003788. PMID:32542862<ref>PMID:32542862</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6zdv" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: Cooke | *[[Adenosine A2A receptor 3D structures|Adenosine A2A receptor 3D structures]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: Gutierrez- | </StructureSection> | ||
[[Category: Jespers | [[Category: Large Structures]] | ||
[[Category: | [[Category: Aqvist J]] | ||
[[Category: | [[Category: Azuaje J]] | ||
[[Category: | [[Category: Congreve M]] | ||
[[Category: | [[Category: Cooke R]] | ||
[[Category: | [[Category: Deflorian F]] | ||
[[Category: | [[Category: Dore A]] | ||
[[Category: De Graaf | [[Category: Garcia-mera X]] | ||
[[Category: Gutierrez-de-Teran H]] | |||
[[Category: Jespers W]] | |||
[[Category: Keranen H]] | |||
[[Category: Majellaro M]] | |||
[[Category: Mason J]] | |||
[[Category: Sotelo E]] | |||
[[Category: Verdon G]] | |||
[[Category: Zhukov A]] | |||
[[Category: De Graaf C]] | |||
Latest revision as of 13:47, 23 October 2024
Crystal structure of stabilized A2A adenosine receptor A2AR-StaR2-bRIL in complex with Chromone 5dCrystal structure of stabilized A2A adenosine receptor A2AR-StaR2-bRIL in complex with Chromone 5d
Structural highlights
Publication Abstract from PubMedWe present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X-ray crystallography to reveal the binding mode of an antagonist series to the A2A adenosine receptor (AR). Eight A2A AR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A2A AR were experimentally determined and investigated through a cycle of ligand-FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X-ray crystallography of the A2A AR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A2A AR, an emerging target in immuno-oncology. X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists.,Jespers W, Verdon G, Azuaje J, Majellaro M, Keranen H, Garcia-Mera X, Congreve M, Deflorian F, de Graaf C, Zhukov A, Dore AS, Mason JS, Aqvist J, Cooke RM, Sotelo E, Gutierrez-de-Teran H Angew Chem Int Ed Engl. 2020 Jun 16. doi: 10.1002/anie.202003788. PMID:32542862[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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