8uap
From Proteopedia
(Difference between revisions)
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<table><tr><td colspan='2'>[[8uap]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8UAP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8UAP FirstGlance]. <br> | <table><tr><td colspan='2'>[[8uap]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8UAP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8UAP 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]] 2.5Å</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]] 2.5Å</td></tr> | ||
| - | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=W2T:( | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=W2T:(3~{Z})-3-[[4-(2-chloranylethanoylamino)-3,5-dimethyl-1~{H}-pyrrol-2-yl]methylidene]-~{N}-[(1~{R})-1-(4-fluorophenyl)ethyl]-2-oxidanylidene-1~{H}-indole-5-carboxamide'>W2T</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=8uap FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8uap OCA], [https://pdbe.org/8uap PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8uap RCSB], [https://www.ebi.ac.uk/pdbsum/8uap PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8uap ProSAT]</span></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=8uap FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8uap OCA], [https://pdbe.org/8uap PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8uap RCSB], [https://www.ebi.ac.uk/pdbsum/8uap PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8uap ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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G protein-coupled receptor kinase 5 (GRK5) is an important drug development target for heart failure, cardiac hypertrophy, and cancer. We have designed and developed a new class of highly selective, potent, and non-covalent GRK5 inhibitors. One of the inhibitors displayed GRK5 IC(50) value of 10 nM and exhibited >100,000-fold selectivity over GRK2. The X-ray structure of a ketoamide-derived inhibitor-bound GRK5 showed the formation of a hemithioketal intermediate with active site Cys474 in the GRK5 active site and provided new insights into the ligand-binding site interactions responsible for high selectivity. The current studies serve as an important guide to therapeutic GRK5 inhibitor drug development. | G protein-coupled receptor kinase 5 (GRK5) is an important drug development target for heart failure, cardiac hypertrophy, and cancer. We have designed and developed a new class of highly selective, potent, and non-covalent GRK5 inhibitors. One of the inhibitors displayed GRK5 IC(50) value of 10 nM and exhibited >100,000-fold selectivity over GRK2. The X-ray structure of a ketoamide-derived inhibitor-bound GRK5 showed the formation of a hemithioketal intermediate with active site Cys474 in the GRK5 active site and provided new insights into the ligand-binding site interactions responsible for high selectivity. The current studies serve as an important guide to therapeutic GRK5 inhibitor drug development. | ||
| - | Development of a new class of potent and highly selective G protein-coupled receptor kinase 5 inhibitors and structural insight from crystal structures of inhibitor complexes.,Chen Y, Sonawane A, Manda R, Gadi RK, Tesmer JJG, Ghosh AK Eur J Med Chem. | + | Development of a new class of potent and highly selective G protein-coupled receptor kinase 5 inhibitors and structural insight from crystal structures of inhibitor complexes.,Chen Y, Sonawane A, Manda R, Gadi RK, Tesmer JJG, Ghosh AK Eur J Med Chem. 2024 Jan 15;264:115931. doi: 10.1016/j.ejmech.2023.115931. Epub , 2023 Nov 10. PMID:38016297<ref>PMID:38016297</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Crystal Structure of Human G Protein-Coupled Receptor Kinase 5 D311N in Complex with CCG273441
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