PDBsum entry 1nkk

Hydrolase/hydrolase inhibitor

PDB id: 1nkk

Contents

Protein chains

222 a.a. *

Ligands

ACE-VAL-DMK-DMH-ALA-CFT ×4

Waters ×249

* Residue conservation analysis

PDB id:

1nkk

Name:

Hydrolase/hydrolase inhibitor

Title:

Complex structure of hcmv protease and a peptidomimetic inhibitor

Structure:

Capsid protein p40. Chain: a, b, c, d. Fragment: assemblin. Synonym: protease, capsid assembly protein. Engineered: yes. Mutation: yes. Peptidomimetic inhibitor. Chain: e, f, g, h. Engineered: yes

Source:

Human herpesvirus 5. Human cytomegalovirus. Organism_taxid: 10359. Gene: ul80 or apng. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: residue peptide of the peptidomimetic inhibitor was chemically synthesized.

Biol. unit:

Tetramer (from PQS)

Resolution:

2.60Å R-factor: 0.233 R-free: 0.280

Authors:

R.Khayat,R.Batra,C.Qian,T.Halmos,M.Bailey,L.Tong

Key ref:

R.Khayat et al. (2003). Structural and biochemical studies of inhibitor binding to human cytomegalovirus protease. Biochemistry, 42, 885-891. PubMed id: 12549906 DOI: 10.1021/bi027045s

Date:

03-Jan-03 Release date: 11-Feb-03

Protein chains

P16753  (SCAF_HCMVA) -  Capsid scaffolding protein from Human cytomegalovirus (strain AD169)

Seq: 708 a.a.

Struc: 222 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.4.21.97 - assemblin.
• Reaction: Cleaves -Ala-|-Ser- and -Ala-|-Ala- bonds in the scaffold protein.

DOI no: 10.1021/bi027045s

Biochemistry 42:885-891 (2003)

PubMed id: 12549906

Structural and biochemical studies of inhibitor binding to human cytomegalovirus protease.

R.Khayat, R.Batra, C.Qian, T.Halmos, M.Bailey, L.Tong.

ABSTRACT

Herpesvirus protease is required for the life cycle of the virus and is an attractive target for the design and development of new anti-herpes agents. The protease belongs to a new class of serine proteases, with a novel backbone fold and a unique Ser-His-His catalytic triad. Here we report the crystal structures of human cytomegalovirus protease in complex with two peptidomimetic inhibitors. The structures reveal a new hydrogen-bonding interaction between the main chain carbonyl of the P(5) residue and the main chain amide of amino acid 137 of the protease, which is important for the binding affinity of the inhibitor. Conformational flexibility was observed in the S(3) pocket of the enzyme, and this is supported by our characterization of several mutants in this pocket. One of the structures is at 2.5 A resolution, allowing us for the first time to locate ordered solvent molecules in the inhibitor complex. The presence of two solvent molecules in the active site may have implications for the design of new inhibitors against this enzyme. Favorable and stereospecific interactions have been established in the S(1)' pocket for one of these inhibitors.