3M5N: Crystal structure of HCV NS3/4A protease in complex with N-terminal product 4B5A

Hepatitis C virus infects an estimated 180 million people worldwide, prompting enormous efforts to develop inhibitors targeting the essential NS3/4A protease. Resistance against the most promising protease inhibitors, telaprevir, boceprevir, and ITMN-191, has emerged in clinical trials. In this study, crystal structures of the NS3/4A protease domain reveal that viral substrates bind to the protease active site in a conserved manner defining a consensus volume, or substrate envelope. Mutations that confer the most severe resistance in the clinic occur where the inhibitors protrude from the substrate envelope, as these changes selectively weaken inhibitor binding without compromising the binding of substrates. These findings suggest a general model for predicting the susceptibility of protease inhibitors to resistance: drugs designed to fit within the substrate envelope will be less susceptible to resistance, as mutations affecting inhibitor binding would simultaneously interfere with the recognition of viral substrates.
PDB ID: 3M5NDownload
MMDB ID: 86430
PDB Deposition Date: 2010/3/12
Updated in MMDB: 2010/12
Experimental Method:
x-ray diffraction
Resolution: 1.9  Å
Source Organism:
Hepatitis C virus subtype 1a
Similar Structures:
Biological Unit for 3M5N: monomeric; determined by author and by software (PISA)
Molecular Components in 3M5N
Label Count Molecule
Protein (1 molecule)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB