5H6V

Structure of Zika virus protease in complex with a dipeptide inhibitor

Summary for 5H6V

• Entry DOI: 10.2210/pdb5h6v/pdb
• NMR Information: BMRB: 26933
• Descriptor: Genome polyprotein, (S)-2-acetamido-6-amino-N-((S)-5-guanidino-1-oxopentan-2-yl)hexanamide, ... (4 entities in total)
• Functional Keywords: serine protease, non-structural protein 3, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Zika virus (ZIKV); More
• Total number of polymer chains: 2
• Total formula weight: 25088.29

Authors

Zhang, Z.,Chen, M. (deposition date: 2016-11-15, release date: 2017-06-14, Last modification date: 2024-11-13)

Primary citation

Li, Y.,Zhang, Z.,Phoo, W.W.,Loh, Y.R.,Wang, W.,Liu, S.,Chen, M.W.,Hung, A.W.,Keller, T.H.,Luo, D.,Kang, C.
Structural Dynamics of Zika Virus NS2B-NS3 Protease Binding to Dipeptide Inhibitors
Structure, 25:1242-1250.e3, 2017

PubMed Abstract: The NS2B-NS3 viral protease is an attractive drug target against Zika virus (ZIKV) due to its importance in viral replication and maturation. Here we report the crystal structure of protease in complex with a dipeptide inhibitor, Acyl-KR-aldehyde (compound 1). The aldehyde moiety forms a covalent bond with the catalytic Ser of NS3. The Arg and Lys residues in the inhibitor occupy the S1 and S2 sites of the protease, respectively. Nuclear magnetic resonance studies demonstrate that the complex is in the closed conformation in solution. The chemical environment of residues surrounding the active site is sensitive to the bound inhibitor as demonstrated by the comparison with two other non-covalent dipeptides, Acyl-K-Agmatine (compound 2) and Acyl-KR-COOH (compound 3). Removing the aldehyde moiety in 1 converts the binding mode from a slow to a fast exchange regime. The structural dynamics information obtained in this study will guide future drug discovery against ZIKV and other flaviviruses.

PubMed: 28689970
DOI: 10.1016/j.str.2017.06.006

Experimental method

X-RAY DIFFRACTION (2.422 Å)