6q2p
Crystal structure of mouse viperin bound to cytidine triphosphate and S-adenosylhomocysteine
Structural highlights
FunctionRSAD2_MOUSE Interferon-inducible iron-sulfur (4FE-4S) cluster-binding antiviral protein which plays a major role in the cell antiviral state induced by type I and type II interferon. Can inhibit a wide range of viruses, including west Nile virus (WNV), dengue virus, sindbis virus, influenza A virus, sendai virus and vesicular stomatitis virus (VSV). Displays antiviral activity against influenza A virus by inhibiting the budding of the virus from the plasma membrane by disturbing the lipid rafts. This is accomplished, at least in part, through binding and inhibition of the enzyme farnesyl diphosphate synthase (FPPS), which is essential for the biosynthesis of isoprenoid-derived lipids. Promotes TLR7 and TLR9-dependent production of IFN-beta production in plasmacytoid dendritic cells (pDCs) by facilitating Lys-63'-linked ubiquitination of IRAK1. Plays a role in CD4+ T-cells activation and differentiation. Facilitates T-cell receptor (TCR)-mediated GATA3 activation and optimal T-helper 2 (Th2) cytokine production by modulating NFKB1 and JUNB activities. Can inhibit secretion of soluble proteins.[1] [2] [3] [4] Publication Abstract from PubMedViperin is a radical S-adenosylmethionine (SAM) enzyme that inhibits viral replication by converting cytidine triphosphate (CTP) into 3'-deoxy-3',4'-didehydro-CTP and by additional undefined mechanisms operating through its N- and C-terminal domains. Here, we describe crystal structures of viperin bound to a SAM analogue and CTP or uridine triphosphate (UTP) and report kinetic parameters for viperin-catalyzed reactions with CTP or UTP as substrates. Viperin orients the C4' hydrogen atom of CTP and UTP similarly for abstraction by a 5'-deoxyadenosyl radical, but the uracil moiety introduces unfavorable interactions that prevent tight binding of UTP. Consistently, kcat is similar for CTP and UTP whereas the Km for UTP is much greater. The structures also show that nucleotide binding results in ordering of the C-terminal tail and reveal that this region contains a P-loop that binds the gamma-phosphate of the bound nucleotide. Collectively, the results explain the selectivity for CTP and reveal a structural role for the C-terminal tail in binding CTP and UTP. Structural Basis of the Substrate Selectivity of Viperin.,Fenwick MK, Su D, Dong M, Lin H, Ealick SE Biochemistry. 2020 Jan 16. doi: 10.1021/acs.biochem.9b00741. PMID:31917549[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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