| http://purl.uniprot.org/citations/33990335 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/33990335 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/33990335 | http://www.w3.org/2000/01/rdf-schema#comment | "Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a major contributor of free energy for oxidative phosphorylation, is increasingly recognized as a promising drug target for ischemia-reperfusion injury, metabolic disorders, and various cancers. Several pharmacologically relevant but structurally unrelated small molecules have been identified as specific complex I inhibitors, but their modes of action remain unclear. Here, we present a 3.0-Å resolution cryo-electron microscopy structure of mammalian complex I inhibited by a derivative of IACS-010759, which is currently in clinical development against cancers reliant on oxidative phosphorylation, revealing its unique cork-in-bottle mechanism of inhibition. We combine structural and kinetic analyses to deconvolute cross-species differences in inhibition and identify the structural motif of a "chain" of aromatic rings as a characteristic that promotes inhibition. Our findings provide insights into the importance of π-stacking residues for inhibitor binding in the long substrate-binding channel in complex I and a guide for future biorational drug design."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.org/dc/terms/identifier | "doi:10.1126/sciadv.abg4000"xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.org/dc/terms/identifier | "doi:10.1126/sciadv.abg4000"xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/author | "Hirst J."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/author | "Hirst J."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/author | "Di Francesco M.E."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/author | "Di Francesco M.E."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/author | "Chung I."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/author | "Chung I."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/author | "Marszalek J.R."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/author | "Marszalek J.R."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/author | "Cross J.B."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/author | "Cross J.B."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/author | "Serreli R."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/author | "Serreli R."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/date | "2021"xsd:gYear |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/date | "2021"xsd:gYear |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/name | "Sci. Adv."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/name | "Sci Adv"xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/pages | "eabg4000"xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/pages | "eabg4000"xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/title | "Cork-in-bottle mechanism of inhibitor binding to mammalian complex I. ."xsd:string |
| http://purl.uniprot.org/citations/33990335 | http://purl.uniprot.org/core/title | "Cork-in-bottle mechanism of inhibitor binding to mammalian complex I."xsd:string |