6EQS
Human Sirt5 in complex with stalled peptidylimidate intermediate of inhibitory compound 29
Summary for 6EQS
| Entry DOI | 10.2210/pdb6eqs/pdb |
| Descriptor | NAD-dependent protein deacylase sirtuin-5, mitochondrial, ZINC ION, 3-[[(~{Z})-~{C}-[(2~{R},3~{R},4~{S},5~{R})-5-[[[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]oxy-oxidanyl-phosphoryl]oxymethyl]-3,4-bis(oxidanyl)oxolan-2-yl]sulfanyl-~{N}-[(5~{S})-6-[[(2~{S})-3-(1~{H}-indol-3-yl)-1-oxidanylidene-1-(propan-2-ylamino)propan-2-yl]amino]-6-oxidanylidene-5-(phenylmethoxycarbonylamino)hexyl]carbonimidoyl]amino]propanoic acid, ... (7 entities in total) |
| Functional Keywords | hydrolase, ptm, inhibitor, signaling protein |
| Biological source | Homo sapiens (Human) |
| Cellular location | Mitochondrion matrix. Isoform 1: Cytoplasm . Isoform 2: Mitochondrion : Q9NXA8 |
| Total number of polymer chains | 4 |
| Total formula weight | 126442.51 |
| Authors | Pannek, M.,Steegborn, C. (deposition date: 2017-10-15, release date: 2017-11-01, Last modification date: 2024-01-17) |
| Primary citation | Rajabi, N.,Auth, M.,Troelsen, K.R.,Pannek, M.,Bhatt, D.P.,Fontenas, M.,Hirschey, M.D.,Steegborn, C.,Madsen, A.S.,Olsen, C.A. Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight. Angew. Chem. Int. Ed. Engl., 56:14836-14841, 2017 Cited by PubMed Abstract: The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more "drug-like" properties. Importantly, enzyme kinetic evaluation revealed a slow, tight-binding mechanism of inhibition, which is unprecedented for SIRT5. This is important information when applying inhibitors to probe mechanisms in biology. PubMed: 29044784DOI: 10.1002/anie.201709050 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.32 Å) |
Structure validation
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