1JQ7

HCMV protease dimer-interface mutant, S225Y complexed to Inhibitor BILC 408

Summary for 1JQ7

• Entry DOI: 10.2210/pdb1jq7/pdb
• Related: 1JQ6 1WPO 2WPO
• Related PRD ID: PRD_000283
• Descriptor: ASSEMBLIN, N-(6-aminohexanoyl)-3-methyl-L-valyl-3-methyl-L-valyl-N~1~-[(2S,3S)-3-hydroxy-4-oxo-4-{[(1R)-1-phenylpropyl]amino}butan-2-yl]-N~4~,N~4~-dimethyl-L-aspartamide (2 entities in total)
• Functional Keywords: herpesvirus, cytomegalovirus, serine protease, dimerization, enzyme activity regulation, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human herpesvirus 5 (Human cytomegalovirus)
• Cellular location: Protease precursor: Host cytoplasm. Assemblin: Host nucleus. Assembly protein: Host nucleus: P16753
• Total number of polymer chains: 2
• Total formula weight: 57849.16

Authors

Batra, R.,Khayat, R.,Tong, L. (deposition date: 2001-08-03, release date: 2001-09-12, Last modification date: 2024-11-20)

Primary citation

Batra, R.,Khayat, R.,Tong, L.
Molecular mechanism for dimerization to regulate the catalytic activity of human cytomegalovirus protease.
Nat.Struct.Biol., 8:810-817, 2001

PubMed Abstract: Biochemical studies indicate that dimerization is required for the catalytic activity of herpesvirus proteases, whereas structural studies show a complete active site in each monomer, away from the dimer interface. Here we report kinetic, biophysical and crystallographic characterizations of structure-based mutants in the dimer interface of human cytomegalovirus (HCMV) protease. Such mutations can produce a 1,700-fold reduction in the kcat while having minimal effects on the K(m). Dimer stability is not affected by these mutations, suggesting that dimerization itself is insufficient for activity. There are large changes in monomer conformation and dimer organization of the apo S225Y mutant enzyme. However, binding of an activated peptidomimetic inhibitor induced a conformation remarkably similar to the wild type protease. Our studies suggest that appropriate dimer formation may be required to indirectly stabilize the protease oxyanion hole, revealing a novel mechanism for dimerization to regulate enzyme activity.

PubMed: 11524687
DOI: 10.1038/nsb0901-810

Experimental method

X-RAY DIFFRACTION (3 Å)