4P3H: Crystal structure of Kaposi's sarcoma-associated herpesvirus (KSHV) protease in complex with dimer disruptor

Citation:
Abstract
Herpesviruses rely on a homodimeric protease for viral capsid maturation. A small molecule, DD2, previously shown to disrupt dimerization of Kaposi's sarcoma-associated herpesvirus protease (KSHV Pr) by trapping an inactive monomeric conformation and two analogues generated through carboxylate bioisosteric replacement (compounds 2 and 3) were shown to inhibit the associated proteases of all three human herpesvirus (HHV) subfamilies (alpha, beta, and gamma). Inhibition data reveal that compound 2 has potency comparable to or better than that of DD2 against the tested proteases. Nuclear magnetic resonance spectroscopy and a new application of the kinetic analysis developed by Zhang and Poorman [Zhang, Z. Y., Poorman, R. A., et al. (1991) J. Biol. Chem. 266, 15591-15594] show DD2, compound 2, and compound 3 inhibit HHV proteases by dimer disruption. All three compounds bind the dimer interface of other HHV proteases in a manner analogous to binding of DD2 to KSHV protease. The determination and analysis of cocrystal structures of both analogues with the KSHV Pr monomer verify and elaborate on the mode of binding for this chemical scaffold, explaining a newly observed critical structure-activity relationship. These results reveal a prototypical chemical scaffold for broad-spectrum allosteric inhibition of human herpesvirus proteases and an approach for the identification of small molecules that allosterically regulate protein activity by targeting protein-protein interactions.
PDB ID: 4P3HDownload
MMDB ID: 121734
PDB Deposition Date: 2014/3/7
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 1.45  Å
Source Organism:
Similar Structures:
Biological Unit for 4P3H: monomeric; determined by author
Molecular Components in 4P3H
Label Count Molecule
Protein (1 molecule)
1
Kshv Protease
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.