6MX0

Crystal structure of human STING apoprotein (G230A, H232R, R293Q)

Summary for 6MX0

• Entry DOI: 10.2210/pdb6mx0/pdb
• Descriptor: Stimulator of interferon genes protein, CALCIUM ION (3 entities in total)
• Functional Keywords: innate immunity, signaling, open conformation, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 43096.41

Authors

Lesburg, C.A.,Siu, T.,Ho, T. (deposition date: 2018-10-30, release date: 2018-12-19, Last modification date: 2023-10-11)

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

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: 30655953
DOI: 10.1021/acsmedchemlett.8b00466

Experimental method

X-RAY DIFFRACTION (1.73 Å)