7tcz | pdb_00007tcz
Human cytomegalovirus protease mutant (C84A, C87A, C138A, C202A) in complex with inhibitor
Structural highlights
Function[A0A126N917_HCMV] Assemblin: Protease that plays an essential role in virion assembly within the nucleus. Catalyzes the cleavage of the assembly protein after formation of the spherical procapsid. By that cleavage, the capsid matures and gains its icosahedral shape. The cleavage sites seem to include -Ala-Ser-, -Ala-Ala-, as well as Ala-Thr bonds. Assemblin and cleavages products are evicted from the capsid before or during DNA packaging.[HAMAP-Rule:MF_04008] Assembly protein: Plays a major role in capsid assembly. Acts as a scaffold protein by binding major capsid protein. Multimerizes in the nucleus such as major capsid protein forms the icosahedral T=16 capsid. Cleaved by assemblin after capsid completion. The cleavages products are evicted from the capsid before or during DNA packaging.[HAMAP-Rule:MF_04008] Capsid scaffolding protein: Acts as a scaffold protein by binding major capsid protein in the cytoplasm, inducing the nuclear localization of both proteins. Multimerizes in the nucleus such as major capsid protein forms the icosahedral T=16 capsid. Autocatalytic cleavage releases the assembly protein, and subsequently abolishes interaction with major capsid protein. Cleavages products are evicted from the capsid before or during DNA packaging.[HAMAP-Rule:MF_04008] Publication Abstract from PubMedViruses are responsible for some of the most deadly human diseases, yet available vaccines and antivirals address only a fraction of the potential viral human pathogens. Here, we provide a methodology for managing human herpesvirus (HHV) infection by covalently inactivating the HHV maturational protease via a conserved, non-catalytic cysteine (C161). Using human cytomegalovirus protease (HCMV Pr) as a model, we screened a library of disulfides to identify molecules that tether to C161 and inhibit proteolysis, then elaborated hits into irreversible HCMV Pr inhibitors that exhibit broad-spectrum inhibition of other HHV Pr homologs. We further developed an optimized tool compound targeted toward HCMV Pr and used an integrative structural biology and biochemical approach to demonstrate inhibitor stabilization of HCMV Pr homodimerization, exploiting a conformational equilibrium to block proteolysis. Irreversible HCMV Pr inhibition disrupts HCMV infectivity in cells, providing proof of principle for targeting proteolysis via a non-catalytic cysteine to manage viral infection. Inhibiting a dynamic viral protease by targeting a non-catalytic cysteine.,Hulce KR, Jaishankar P, Lee GM, Bohn MF, Connelly EJ, Wucherer K, Ongpipattanakul C, Volk RF, Chuo SW, Arkin MR, Renslo AR, Craik CS Cell Chem Biol. 2022 Mar 30. pii: S2451-9456(22)00124-6. doi:, 10.1016/j.chembiol.2022.03.007. PMID:35364007[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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