6UL0

STING C-terminal Domain Complexed with Non-cyclic Dinucleotide Compound 4

Summary for 6UL0

• Entry DOI: 10.2210/pdb6ul0/pdb
• Descriptor: fusion protein of Ubiquitin-like protein SMT3 and Stimulator of interferon protein c-terminal domain, 4-{5-[(1Z)-3-{[2-(3-carboxypropanoyl)-6-methoxy-1-benzothiophen-5-yl]oxy}prop-1-en-1-yl]-6-methoxy-1-benzothiophen-2-yl}-4-oxobutanoic acid (3 entities in total)
• Functional Keywords: agonist, sting (stimulator of interferon genes), transmembrane protein 173 (tmem173), immune system, immune system-inhibitor complex, immune system-agonist complex
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast); More
• Total number of polymer chains: 1
• Total formula weight: 35039.17

Authors

Lesburg, C.A. (deposition date: 2019-10-06, release date: 2020-08-19, Last modification date: 2023-10-11)

Primary citation

Pan, B.S.,Perera, S.A.,Piesvaux, J.A.,Presland, J.P.,Schroeder, G.K.,Cumming, J.N.,Trotter, B.W.,Altman, M.D.,Buevich, A.V.,Cash, B.,Cemerski, S.,Chang, W.,Chen, Y.,Dandliker, P.J.,Feng, G.,Haidle, A.,Henderson, T.,Jewell, J.,Kariv, I.,Knemeyer, I.,Kopinja, J.,Lacey, B.M.,Laskey, J.,Lesburg, C.A.,Liang, R.,Long, B.J.,Lu, M.,Ma, Y.,Minnihan, E.C.,O'Donnell, G.,Otte, R.,Price, L.,Rakhilina, L.,Sauvagnat, B.,Sharma, S.,Tyagarajan, S.,Woo, H.,Wyss, D.F.,Xu, S.,Bennett, D.J.,Addona, G.H.
An orally available non-nucleotide STING agonist with antitumor activity.
Science, 369:-, 2020

PubMed Abstract: Pharmacological activation of the STING (stimulator of interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report the identification of MSA-2, an orally available non-nucleotide human STING agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated and stimulated interferon-β secretion in tumors, induced tumor regression with durable antitumor immunity, and synergized with anti-PD-1 therapy. Experimental and theoretical analyses showed that MSA-2 exists as interconverting monomers and dimers in solution, but only dimers bind and activate STING. This model was validated by using synthetic covalent MSA-2 dimers, which were potent agonists. Cellular potency of MSA-2 increased upon extracellular acidification, which mimics the tumor microenvironment. These properties appear to underpin the favorable activity and tolerability profiles of effective systemic administration of MSA-2.

PubMed: 32820094
DOI: 10.1126/science.aba6098

Experimental method

X-RAY DIFFRACTION (1.76 Å)