8u7h
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Cryo-EM structure of LRRK2 bound to type I inhibitor GNE-7915== | |
| + | <StructureSection load='8u7h' size='340' side='right'caption='[[8u7h]], [[Resolution|resolution]] 3.80Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8u7h]] 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=8U7H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8U7H FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.8Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A0T:[4-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-2-fluoranyl-5-methoxy-phenyl]-morpholin-4-yl-methanone'>A0T</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</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=8u7h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8u7h OCA], [https://pdbe.org/8u7h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8u7h RCSB], [https://www.ebi.ac.uk/pdbsum/8u7h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8u7h ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/Q17RV3_HUMAN Q17RV3_HUMAN] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | LRRK2 is one of the most promising drug targets for Parkinson's disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being actively pursued due to the potential undesired effects of type I inhibitors. Currently, a robust method for LRRK2-inhibitor structure determination to guide structure-based drug discovery is lacking, and inhibition mechanisms of available compounds are also unclear. Here we present near-atomic-resolution structures of LRRK2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors, uncovering the structural basis of LRRK2 inhibition and conformational plasticity of the kinase domain with molecular dynamics (MD) simulations. Type I and II inhibitors bind to LRRK2 in active-like and inactive conformations, so LRRK2-inhibitor complexes further reveal general structural features associated with LRRK2 activation. Our study provides atomic details of LRRK2-inhibitor interactions and a framework for understanding LRRK2 activation and for rational drug design. | ||
| - | + | Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM.,Zhu H, Hixson P, Ma W, Sun J Cell Discov. 2024 Jan 23;10(1):10. doi: 10.1038/s41421-023-00639-8. PMID:38263358<ref>PMID:38263358</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8u7h" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Sun J]] | ||
| + | [[Category: Zhu H]] | ||
Current revision
Cryo-EM structure of LRRK2 bound to type I inhibitor GNE-7915
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