Structural highlights
Publication Abstract from PubMedCyclic dinucleotides are second messengers in the cGAS-STING pathway which plays an important role in recognizing tumor cells and viral or bacterial infections. They bind to STING adaptor protein and trigger expression of cytokines via TBK1/IRF3 and IKK/NFkappaB signaling cascades. In this report we describe an enzymatic preparation of 2'-5', 3'-5' cyclic dinucleotides (2'3'CDNs) with use of cyclic GMP-AMP synthases (cGAS) from human, mouse and chicken. We profile substrate specificity of these enzymes by employing a small library of NTP analogues and use them to prepare thirty-three 2'3'CDNs. We also determine affinity of these CDNs to five different STING haplotypes in cell-based and biochemical assays, and describe properties needed for their optimal activity toward all STING haplotypes. Next, we study their effect on cytokines and chemokines induction by human peripheral blood mononuclear cells (PBMCs) and evaluate their cytotoxic effect on monocytes. Additionally, we report X-ray crystal structures of two new CDNs bound to STING protein and discuss structure activity relationship by using quantum and molecular mechanical (QM/MM) computational modeling. Enzymatic Preparation of 2'-5', 3'-5'Cyclic Dinucleotides, Their Binding Properties to STING Adaptor Protein, and Structure/Activity Correlations.,Novotna B, Vanekova L, Zavrel M, Budesinsky M, Dejmek M, Smola M, Gutten O, Tehrani ZA, Pimkova Polidarova M, Brazdova A, Liboska R, Stepanek I, Vavrina Z, Jandusik T, Nencka R, Rulisek L, Boura E, Brynda J, Pav O, Birkus G J Med Chem. 2019 Nov 12. doi: 10.1021/acs.jmedchem.9b01062. PMID:31715099[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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