4P3H

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

Summary for 4P3H

• Entry DOI: 10.2210/pdb4p3h/pdb
• Related: 4P2T
• Descriptor: KSHV protease, N-[2-benzyl-4-(1H-tetrazol-5-yl)phenyl]-6-(cyclohexylmethyl)pyridine-2-carboxamide, GLYCEROL, ... (5 entities in total)
• Functional Keywords: protein-protein interaction inhibition, serine protease, inhibitor complex, beta barrel and alpha helices, hydrolase
• Biological source: Human herpesvirus 8 (HHV-8)
• Total number of polymer chains: 2
• Total formula weight: 43992.24

Authors

Gable, J.E. (deposition date: 2014-03-07, release date: 2014-07-23, Last modification date: 2023-09-27)

Primary citation

Gable, J.E.,Lee, G.M.,Jaishankar, P.,Hearn, B.R.,Waddling, C.A.,Renslo, A.R.,Craik, C.S.
Broad-spectrum allosteric inhibition of herpesvirus proteases.
Biochemistry, 53:4648-4660, 2014

PubMed 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 (α, β, and γ). 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.

PubMed: 24977643
DOI: 10.1021/bi5003234

Experimental method

X-RAY DIFFRACTION (1.45 Å)