PDBsum entry 5eqs

Hydrolase/hydrolase inhibitor

PDB id: 5eqs

Contents

Protein chain

192 a.a.

Ligands

2R9

Metals

_ZN

Waters ×33

PDB id:

5eqs

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of a genotype 1a/3a chimeric hcv ns3/4a protease in complex with asunaprevir

Structure:

Ns3 protease. Chain: a. Engineered: yes. Mutation: yes

Source:

Hepatitis c virus. Organism_taxid: 11103. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.84Å R-factor: 0.198 R-free: 0.245

Authors:

D.Soumana,N.K.Yilmaz,A.Ali,K.L.Prachanronarong,C.A.Schiffer

Key ref:

D.I.Soumana et al. (2016). Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease. J Am Chem Soc, 138, 11850-11859. PubMed id: 27512818 DOI: 10.1021/jacs.6b06454

Date:

13-Nov-15 Release date: 23-Nov-16

Protein chain

A0A0B4WYC6  (A0A0B4WYC6_9HEPC) -  Genome polyprotein (Fragment) from Hepacivirus C

Seq: 182 a.a.

Struc: 192 a.a.*

* PDB and UniProt seqs differ at 15 residue positions (black crosses)

DOI no: 10.1021/jacs.6b06454

J Am Chem Soc 138:11850-11859 (2016)

PubMed id: 27512818

Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease.

D.I.Soumana, N.Kurt Yilmaz, A.Ali, K.L.Prachanronarong, C.A.Schiffer.

ABSTRACT

Hepatitis C virus (HCV), affecting an estimated 150 million people worldwide, is the leading cause of viral hepatitis, cirrhosis and hepatocellular carcinoma. HCV is genetically diverse with six genotypes (GTs) and multiple subtypes of different global distribution and prevalence. Recent development of direct-acting antivirals against HCV including NS3/4A protease inhibitors (PIs) has greatly improved treatment outcomes for GT-1. However, all current PIs exhibit significantly lower potency against GT-3. Lack of structural data on GT-3 protease has limited our ability to understand PI failure in GT-3. In this study the molecular basis for reduced potency of current inhibitors against GT-3 NS3/4A protease is elucidated with structure determination, molecular dynamics simulations and inhibition assays. A chimeric GT-1a3a NS3/4A protease amenable to crystallization was engineered to recapitulate decreased sensitivity of GT-3 protease to PIs. High-resolution crystal structures of this GT-1a3a bound to 3 PIs, asunaprevir, danoprevir and vaniprevir, had only subtle differences relative to GT-1 despite orders of magnitude loss in affinity. In contrast, hydrogen-bonding interactions within and with the protease active site and dynamic fluctuations of the PIs were drastically altered. The correlation between loss of intermolecular dynamics and inhibitor potency suggests a mechanism where polymorphisms between genotypes (or selected mutations) in the drug target confer resistance through altering the intermolecular dynamics of the protein-inhibitor complex.