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PDBsum entry 5eqs
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Hydrolase/hydrolase inhibitor
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PDB id
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5eqs
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References listed in PDB file
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Key reference
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Title
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Molecular and dynamic mechanism underlying drug resistance in genotype 3 hepatitis c ns3/4a protease.
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Authors
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D.I.Soumana,
N.Kurt yilmaz,
A.Ali,
K.L.Prachanronarong,
C.A.Schiffer.
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Ref.
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J Am Chem Soc, 2016,
138,
11850-11859.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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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.
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Secondary reference #1
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Title
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Structural analysis of asunaprevir resistance in hcv ns3/4a protease.
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Authors
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D.I.Soumana,
A.Ali,
C.A.Schiffer.
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Ref.
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Acs Chem Biol, 2014,
9,
2485-2490.
[DOI no: ]
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PubMed id
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