PDBsum entry 5v5e

Viral protein / inhibitor

PDB id: 5v5e

Contents

Protein chains

188 a.a.

Ligands

8N4 ×3

Waters ×43

PDB id:

5v5e

Name:

Viral protein / inhibitor

Title:

Room temperature (280k) crystal structure of kaposi's sarcoma- associated herpesvirus protease in complex with allosteric inhibitor (compound 733)

Structure:

Orf 17. Chain: a, b. Fragment: residues 23-215. Synonym: orf17. Engineered: yes

Source:

Human herpesvirus 8. Hhv-8. Organism_taxid: 37296. Gene: orf17. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.30Å R-factor: 0.200 R-free: 0.230

Authors:

M.C.Thompson,T.M.Acker,J.S.Fraser,C.S.Craik

Key ref:

T.M.Acker et al. (2017). Allosteric Inhibitors, Crystallography, and Comparative Analysis Reveal Network of Coordinated Movement across Human Herpesvirus Proteases. J Am Chem Soc, 139, 11650-11653. PubMed id: 28759216 DOI: 10.1021/jacs.7b04030

Date:

14-Mar-17 Release date: 12-Apr-17

Protein chains

O40922  (O40922_HHV8) -  Capsid scaffolding protein from Human herpesvirus 8

Seq: 553 a.a.

Struc: 188 a.a.

DOI no: 10.1021/jacs.7b04030

J Am Chem Soc 139:11650-11653 (2017)

PubMed id: 28759216

Allosteric Inhibitors, Crystallography, and Comparative Analysis Reveal Network of Coordinated Movement across Human Herpesvirus Proteases.

T.M.Acker, J.E.Gable, M.F.Bohn, P.Jaishankar, M.C.Thompson, J.S.Fraser, A.R.Renslo, C.S.Craik.

ABSTRACT

Targeting of cryptic binding sites represents an attractive but underexplored approach to modulating protein function with small molecules. Using the dimeric protease (Pr) from Kaposi's sarcoma-associated herpesvirus (KSHV) as a model system, we sought to dissect a putative allosteric network linking a cryptic site at the dimerization interface to enzyme function. Five cryogenic X-ray structures were solved of the monomeric protease with allosteric inhibitors bound to the dimer interface site. Distinct coordinated movements captured by the allosteric inhibitors were also revealed as alternative states in room-temperature X-ray data and comparative analyses of other dimeric herpesvirus proteases. A two-step mechanism was elucidated through detailed kinetic analyses and suggests an enzyme isomerization model of inhibition. Finally, a representative allosteric inhibitor from this class was shown to be efficacious in a cellular model of viral infectivity. These studies reveal a coordinated dynamic network of atomic communication linking cryptic binding site occupancy and allosteric inactivation of KHSV Pr that can be exploited to target other members of this clinically relevant family of enzymes.