Human cytomegalovirus protease complexes its substrate recognition sequences in an extended peptide conformation

Biochemistry
S R LaPlanteF Ni

Abstract

Substrate hydrolysis by human cytomegalovirus (HCMV) protease is essential to viral capsid assembly. The interaction of HCMV protease and the N-terminal cleavage products of the hydrolysis of R- and M-site oligopeptide substrate mimics (R and M, respectively, which span the P9-P1 positions) was studied by NMR methods. Protease-induced differential line broadening indicated that ligand binding is mediated by the P4-P1 amino acid residues of the peptides. A well-defined extended conformation of R from P1 through P4 when complexed to HCMV protease was evidenced by numerous transferred nuclear Overhauser effect (NOE) correlations for the peptide upon addition of the enzyme. NOE cross-peaks between the P4 and P5 side chains placing these two groups in proximity indicated a deviation from the extended conformation starting at P5. Similar studies carried out for the M peptide also indicated an extended peptide structure very similar to that of R, although the conformation of the P5 glycine could not be established. No obvious variation in structure between bound R and M (notably at P4, where the tyrosine of the R-site has been suggested to play a key role in ligand binding) could be discerned that might explain the observed difference...Continue Reading

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Citations

Apr 13, 2001·Medicinal Research Reviews·A MartinezC Perez
Feb 27, 1999·Current Opinion in Biotechnology·G C Roberts
Mar 15, 2013·Molecular Pharmaceutics·Hairat SabitGordon L Amidon
Sep 18, 2007·Journal of Molecular Biology·Ana LazicCharles S Craik
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Mar 10, 2005·Chemical Reviews·Joel D A TyndallDavid P Fairlie
Apr 10, 2010·Chemical Reviews·Praveen K MadalaDavid P Fairlie
Dec 12, 2002·Chemical Reviews·Liang Tong

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