8QNG
Crystal structure of the E3 ubiquitin ligase Cbl-b with an allosteric inhibitor (benzodiazepine HTS hit compound 1)
Summary for 8QNG
| Entry DOI | 10.2210/pdb8qng/pdb |
| Descriptor | E3 ubiquitin-protein ligase CBL-B, 2-(morpholin-4-ylmethyl)-~{N}-[(3~{S})-2-oxidanylidene-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]benzamide, ZINC ION, ... (5 entities in total) |
| Functional Keywords | e3 ubiquitin ligase, allosteric inhibition, structure based drug design, ligase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 46417.84 |
| Authors | Schimpl, M. (deposition date: 2023-09-26, release date: 2023-11-22, Last modification date: 2024-01-03) |
| Primary citation | Boerth, J.A.,Chinn, A.J.,Schimpl, M.,Bommakanti, G.,Chan, C.,Code, E.L.,Giblin, K.A.,Gohlke, A.,Hansel, C.S.,Jin, M.,Kavanagh, S.L.,Lamb, M.L.,Lane, J.S.,Larner, C.J.B.,Mfuh, A.M.,Moore, R.K.,Puri, T.,Quinn, T.R.,Ye, M.,Robbins, K.J.,Gancedo-Rodrigo, M.,Tang, H.,Walsh, J.,Ware, J.,Wrigley, G.L.,Reddy, I.K.,Zhang, Y.,Grimster, N.P. Discovery of a Novel Benzodiazepine Series of Cbl-b Inhibitors for the Enhancement of Antitumor Immunity. Acs Med.Chem.Lett., 14:1848-1856, 2023 Cited by PubMed Abstract: Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that is responsible for repressing T-cell, natural killer (NK) cell, and B-cell activation. The robust antitumor activity observed in Cbl-b deficient mice arising from elevated T-cell and NK-cell activity justified our discovery effort toward Cbl-b inhibitors that might show therapeutic promise in immuno-oncology, where activation of the immune system can drive the recognition and killing of cancer cells. We undertook a high-throughput screening campaign followed by structure-enabled optimization to develop a novel benzodiazepine series of potent Cbl-b inhibitors. This series displayed nanomolar levels of biochemical potency, as well as potent T-cell activation. The functional activity of this class of Cbl-b inhibitors was further corroborated with ubiquitin-based cellular assays. PubMed: 38116444DOI: 10.1021/acsmedchemlett.3c00439 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.197 Å) |
Structure validation
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