5v5d

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

spinqualitylabelsall models 5v5d, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5v5d is a 2 chain structure with sequence from Hhv-8. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 8OY Gene: ORF17 (HHV-8) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Allosteric Inhibitors, Crystallography and Comparative Analysis Reveal Network of Coordinated Movement Across Human Herpesvirus Proteases.,Acker TM, Gable JE, Bohn MF, Jaishankar P, Thompson MC, Fraser JS, Renslo AR, Craik CS J Am Chem Soc. 2017 Jul 31. doi: 10.1021/jacs.7b04030. PMID:28759216 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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