6MXE
Crystal structure of human STING (G230A, H232R, R293Q) in complex with Compound 18
Summary for 6MXE
| Entry DOI | 10.2210/pdb6mxe/pdb |
| Descriptor | Stimulator of interferon genes protein, [(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]acetic acid, CALCIUM ION, ... (4 entities in total) |
| Functional Keywords | innate immunity, signaling, open conformation, immune system, immune system-inhibitor complex, immune system/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 44184.45 |
| Authors | Lesburg, C.A.,Siu, T.,Ho, T. (deposition date: 2018-10-30, release date: 2018-12-19, Last modification date: 2024-03-13) |
| Primary citation | Siu, T.,Altman, M.D.,Baltus, G.A.,Childers, M.,Ellis, J.M.,Gunaydin, H.,Hatch, H.,Ho, T.,Jewell, J.,Lacey, B.M.,Lesburg, C.A.,Pan, B.S.,Sauvagnat, B.,Schroeder, G.K.,Xu, S. Discovery of a Novel cGAMP Competitive Ligand of the Inactive Form of STING. ACS Med Chem Lett, 10:92-97, 2019 Cited by PubMed Abstract: Drugging large protein pockets is a challenge due to the need for higher molecular weight ligands, which generally possess undesirable physicochemical properties. In this communication, we highlight a strategy leveraging small molecule active site dimers to inhibit the large symmetric binding pocket in the STING protein. By taking advantage of the 2:1 binding stoichiometry, maximal buried interaction with STING protein can be achieved while maintaining the ligand physicochemical properties necessary for oral exposure. This mode of binding requires unique considerations for potency optimization including simultaneous optimization of protein-ligand as well as ligand-ligand interactions. Successful implementation of this strategy led to the identification of , which exhibits good oral exposure, slow binding kinetics, and functional inhibition of STING-mediated cytokine release. PubMed: 30655953DOI: 10.1021/acsmedchemlett.8b00466 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.47 Å) |
Structure validation
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