7MHC

Structure of human STING in complex with MK-1454

Summary for 7MHC

• Entry DOI: 10.2210/pdb7mhc/pdb
• Descriptor: Stimulator of interferon genes protein, (2R,5R,7R,8S,10R,12aR,14R,15S,15aR,16R)-7-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-14-(6-amino-9H-purin-9-yl)-15,16-difluoro-2,10-bis(sulfanyl)octahydro-2H,10H,12H-5,8-methano-2lambda~5~,10lambda~5~-furo[3,2-l][1,3,6,9,11,2,10]pentaoxadiphosphacyclotetradecine-2,10-dione (3 entities in total)
• Functional Keywords: sting, receptor, ligand complex, agonist, closed conformation, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 22263.70

Authors

Lesburg, C.A. (deposition date: 2021-04-15, release date: 2022-04-06, Last modification date: 2023-10-18)

Primary citation

McIntosh, J.A.,Liu, Z.,Andresen, B.M.,Marzijarani, N.S.,Moore, J.C.,Marshall, N.M.,Borra-Garske, M.,Obligacion, J.V.,Fier, P.S.,Peng, F.,Forstater, J.H.,Winston, M.S.,An, C.,Chang, W.,Lim, J.,Huffman, M.A.,Miller, S.P.,Tsay, F.R.,Altman, M.D.,Lesburg, C.A.,Steinhuebel, D.,Trotter, B.W.,Cumming, J.N.,Northrup, A.,Bu, X.,Mann, B.F.,Biba, M.,Hiraga, K.,Murphy, G.S.,Kolev, J.N.,Makarewicz, A.,Pan, W.,Farasat, I.,Bade, R.S.,Stone, K.,Duan, D.,Alvizo, O.,Adpressa, D.,Guetschow, E.,Hoyt, E.,Regalado, E.L.,Castro, S.,Rivera, N.,Smith, J.P.,Wang, F.,Crespo, A.,Verma, D.,Axnanda, S.,Dance, Z.E.X.,Devine, P.N.,Tschaen, D.,Canada, K.A.,Bulger, P.G.,Sherry, B.D.,Truppo, M.D.,Ruck, R.T.,Campeau, L.C.,Bennett, D.J.,Humphrey, G.R.,Campos, K.R.,Maddess, M.L.
A kinase-cGAS cascade to synthesize a therapeutic STING activator.
Nature, 603:439-444, 2022

PubMed Abstract: The introduction of molecular complexity in an atom- and step-efficient manner remains an outstanding goal in modern synthetic chemistry. Artificial biosynthetic pathways are uniquely able to address this challenge by using enzymes to carry out multiple synthetic steps simultaneously or in a one-pot sequence. Conducting biosynthesis ex vivo further broadens its applicability by avoiding cross-talk with cellular metabolism and enabling the redesign of key biosynthetic pathways through the use of non-natural cofactors and synthetic reagents. Here we describe the discovery and construction of an enzymatic cascade to MK-1454, a highly potent stimulator of interferon genes (STING) activator under study as an immuno-oncology therapeutic (ClinicalTrials.gov study NCT04220866 ). From two non-natural nucleotide monothiophosphates, MK-1454 is assembled diastereoselectively in a one-pot cascade, in which two thiotriphosphate nucleotides are simultaneously generated biocatalytically, followed by coupling and cyclization catalysed by an engineered animal cyclic guanosine-adenosine synthase (cGAS). For the thiotriphosphate synthesis, three kinase enzymes were engineered to develop a non-natural cofactor recycling system in which one thiotriphosphate serves as a cofactor in its own synthesis. This study demonstrates the substantial capacity that currently exists to use biosynthetic approaches to discover and manufacture complex, non-natural molecules.

PubMed: 35296845
DOI: 10.1038/s41586-022-04422-9

Experimental method

X-RAY DIFFRACTION (2.32 Å)