6mx3 | pdb_00006mx3
Crystal structure of human STING (G230A, H232R, R293Q) in complex with Compound 1
Structural highlights
Function[STING_HUMAN] Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm. Acts by recognizing and binding cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced in response to DNA virus in the cytosol: upon binding of c-di-GMP or cGAMP, autoinhibition is alleviated and TMEM173/STING is able to activate both NF-kappa-B and IRF3 transcription pathways to induce expression of type I interferon and exert a potent anti-viral state. May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons. May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II). Mediates death signaling via activation of the extracellular signal-regulated kinase (ERK) pathway.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedDrugging 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 18, which exhibits good oral exposure, slow binding kinetics, and functional inhibition of STING-mediated cytokine release. Discovery of a Novel cGAMP Competitive Ligand of the Inactive Form of STING.,Siu T, Altman MD, Baltus GA, Childers M, Ellis JM, Gunaydin H, Hatch H, Ho T, Jewell J, Lacey BM, Lesburg CA, Pan BS, Sauvagnat B, Schroeder GK, Xu S ACS Med Chem Lett. 2018 Dec 6;10(1):92-97. doi: 10.1021/acsmedchemlett.8b00466., eCollection 2019 Jan 10. PMID:30655953[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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