5V5D

Room temperature (280K) crystal structure of Kaposi's sarcoma-associated herpesvirus protease in complex with allosteric inhibitor (compound 250)

5V5D の概要

• エントリーDOI: 10.2210/pdb5v5d/pdb
• 分子名称: ORF 17, 4-{[6-(cyclohexylmethyl)pyridine-2-carbonyl]amino}-3-(phenylamino)benzoic acid (3 entities in total)
• 機能のキーワード: protease, allosteric inhibitor, herpesvirus, viral protein - inhibitor complex, viral protein / inhibitor
• 由来する生物種: Human herpesvirus 8 (HHV-8)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 43674.76

構造登録者

Thompson, M.C.,Acker, T.M.,Fraser, J.S.,Craik, C.S. (登録日: 2017-03-14, 公開日: 2017-04-12, 最終更新日: 2023-10-04)

主引用文献

Acker, T.M.,Gable, J.E.,Bohn, M.F.,Jaishankar, P.,Thompson, M.C.,Fraser, J.S.,Renslo, A.R.,Craik, C.S.
Allosteric Inhibitors, Crystallography, and Comparative Analysis Reveal Network of Coordinated Movement across Human Herpesvirus Proteases.
J. Am. Chem. Soc., 139:11650-11653, 2017

PubMed 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.

PubMed: 28759216
DOI: 10.1021/jacs.7b04030

実験手法

X-RAY DIFFRACTION (2.104 Å)