7TCZ

Human cytomegalovirus protease mutant (C84A, C87A, C138A, C202A) in complex with inhibitor

Summary for 7TCZ

• Entry DOI: 10.2210/pdb7tcz/pdb
• Descriptor: Assemblin, [1-(2-oxopropyl)-4-phenyl-1H-1,2,3-triazol-5-yl]methyl benzylcarbamate (3 entities in total)
• Functional Keywords: protease, viral protein, hyrdrolase-hydrolase inhibitor complex, hyrdrolase/hydrolase inhibitor
• Biological source: Human betaherpesvirus 5
• Total number of polymer chains: 1
• Total formula weight: 29325.81

Authors

Hulce, K.R.,Bohn, M.,Ongpipattanakul, C.,Jaishankar, P.,Renslo, A.R.,Craik, C.S. (deposition date: 2021-12-29, release date: 2022-01-12, Last modification date: 2024-10-23)

Primary citation

Hulce, K.R.,Jaishankar, P.,Lee, G.M.,Bohn, M.F.,Connelly, E.J.,Wucherer, K.,Ongpipattanakul, C.,Volk, R.F.,Chuo, S.W.,Arkin, M.R.,Renslo, A.R.,Craik, C.S.
Inhibiting a dynamic viral protease by targeting a non-catalytic cysteine.
Cell Chem Biol, 29:785-798.e19, 2022

PubMed Abstract: Viruses 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.

PubMed: 35364007
DOI: 10.1016/j.chembiol.2022.03.007

Experimental method

X-RAY DIFFRACTION (2.67 Å)