6Z10
Crystal structure of a humanized (K18E, K269N) rat succinate receptor SUCNR1 (GPR91) in complex with a nanobody and antagonist
Summary for 6Z10
| Entry DOI | 10.2210/pdb6z10/pdb |
| Descriptor | Succinate receptor 1, Nanobody6, 2-[2-[[3-[4-chloranyl-2-fluoranyl-5-[(3~{R})-piperidin-3-yl]oxy-phenyl]-2-fluoranyl-phenyl]carbonylamino]-5-fluoranyl-phenyl]ethanoic acid, ... (7 entities in total) |
| Functional Keywords | g protein-coupled receptor gpcr succinate receptor, membrane protein |
| Biological source | Rattus norvegicus (Rat) More |
| Total number of polymer chains | 2 |
| Total formula weight | 60283.68 |
| Authors | Haffke, M.,Villard, F. (deposition date: 2020-05-11, release date: 2020-09-16, Last modification date: 2024-11-20) |
| Primary citation | Velcicky, J.,Wilcken, R.,Cotesta, S.,Janser, P.,Schlapbach, A.,Wagner, T.,Piechon, P.,Villard, F.,Bouhelal, R.,Piller, F.,Harlfinger, S.,Stringer, R.,Fehlmann, D.,Kaupmann, K.,Littlewood-Evans, A.,Haffke, M.,Gommermann, N. Discovery and Optimization of Novel SUCNR1 Inhibitors: Design of Zwitterionic Derivatives with a Salt Bridge for the Improvement of Oral Exposure. J.Med.Chem., 63:9856-9875, 2020 Cited by PubMed Abstract: G-protein-coupled receptor SUCNR1 (succinate receptor 1 or GPR91) senses the citric cycle intermediate succinate and is implicated in various pathological conditions such as rheumatoid arthritis, liver fibrosis, or obesity. Here, we describe a novel SUCNR1 antagonist scaffold discovered by high-throughput screening. The poor permeation and absorption properties of the most potent compounds, which were zwitterionic in nature, could be improved by the formation of an internal salt bridge, which helped in shielding the two opposite charges and thus also the high polarity of zwitterions with separated charges. The designed compounds containing such a salt bridge reached high oral bioavailability and oral exposure. We believe that this principle could find a broad interest in the medicinal chemistry field as it can be useful not only for the modulation of properties in zwitterionic compounds but also in acidic or basic compounds with poor permeation. PubMed: 32856916DOI: 10.1021/acs.jmedchem.0c01020 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.269 Å) |
Structure validation
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