1DY9

Inhibition of the Hepatitis C Virus NS3/4A Protease. The Crystal Structures of Two Protease-Inhibitor Complexes (inhibitor I)

PDB DOI: https://doi.org/10.2210/pdb1DY9/pdb

Classification: HYDROLASE/HYDROLASE INHIBITOR
Organism(s): Hepatitis C virus (isolate Taiwan)
Expression System: Escherichia coli BL21(DE3)
Mutation(s): Yes

Deposited: 2000-01-31 Released: 2001-01-28
Deposition Author(s): Di Marco, S., Rizzi, M., Volpari, C., Walsh, M., Narjes, F., Colarusso, S., De Francesco, R., Matassa, V.G., Sollazzo, M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.10 Å
R-Value Free: 0.275
R-Value Work: 0.213
R-Value Observed: 0.207

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.5 of the entry. See complete history.

Literature

Inhibition of the Hepatitis C Virus Ns3/4A Protease the Crystal Structures of Two Protease-Inhibitor Complexes

Di Marco, S., Rizzi, M., Volpari, C., Walsh, M., Narjes, F., Colarusso, S., De Francesco, R., Matassa, V.G., Sollazzo, M.

(2000) J Biol Chem 275: 7152

PubMed: 10702283 Search on PubMed
DOI: https://doi.org/10.1074/jbc.275.10.7152
Primary Citation of Related Structures:
1DXP, 1DY8, 1DY9

PubMed Abstract:
The hepatitis C virus NS3 protein contains a serine protease domain with a chymotrypsin-like fold, which is a target for development of therapeutics. We report the crystal structures of this domain complexed with NS4A cofactor and with two potent, reversible covalent inhibitors spanning the P1-P4 residues. Both inhibitors bind in an extended backbone conformation, forming an anti-parallel beta-sheet with one enzyme beta-strand. The P1 residue contributes most to the binding energy, whereas P2-P4 side chains are partially solvent exposed. The structures do not show notable rearrangements of the active site upon inhibitor binding. These results are significant for the development of antivirals.

Organizational Affiliation

Biotechnology, Via Pontina Km 30.600, 00040 Pomezia, Rome, Italy.

Macromolecule Content

Total Structure Weight: 43.96 kDa
Atom Count: 3,018
Modelled Residue Count: 374
Deposited Residue Count: 406
Unique protein chains: 2

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
PROTEASE/HELICASE NS3 (P70)	A, B	187	Hepatitis C virus (isolate Taiwan)	Mutation(s): 0 Gene Names: HCV EC: 3.4.22
UniProt
Find proteins for P26662 (Hepatitis C virus genotype 1b (isolate Japanese)) Explore P26662 Go to UniProtKB: P26662
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P26662
Sequence Annotations Expand
Reference Sequence

Find similar proteins by: Sequence | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
NONSTRUCTURAL PROTEIN NS4A (P4)	C, D	16	Hepatitis C virus (isolate Taiwan)	Mutation(s): 2
UniProt
Find proteins for P26662 (Hepatitis C virus genotype 1b (isolate Japanese)) Explore P26662 Go to UniProtKB: P26662
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P26662
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
2ZF Query on 2ZF Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth B] MOL2 format, chain E [auth A] MOL2 format, chain F [auth B]	E [auth A], F [auth B]	N-(tert-butoxycarbonyl)-L-alpha-glutamyl-N-[(1R)-1-(carboxycarbonyl)-3,3-difluoropropyl]-L-leucinamide C₂₁ H₃₃ F₂ N₃ O₉ WXVMZATZAOHPFR-AVGNSLFASA-N		Interactions Focus chain E [auth A] Focus chain F [auth B] Interactions & Density Focus chain E [auth A] Focus chain F [auth B]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain G [auth B] MOL2 format, chain G [auth B]	G [auth B]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain G [auth B] Interactions & Density Focus chain G [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
2ZF	BindingDB: 1DY9	IC50: 330 (nM) from 1 assay(s)

Biologically Interesting Molecules (External Reference) 1 Unique

Entity ID: 3
ID	Chains	Name	Type/Class	2D Diagram	3D Interactions
PRD_000426 (2ZF) Query on PRD_000426	E [auth A], F [auth B]	BOC-GLU-LEU-FKI, PEPTIDE INHIBITOR	Peptide-like / Inhibitor		Interactions Focus chain E [auth A] Focus chain F [auth B] Interactions & Density Focus chain E [auth A] Focus chain F [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.10 Å
R-Value Free: 0.275
R-Value Work: 0.213
R-Value Observed: 0.207
Space Group: P 6₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 94.35	α = 90
b = 94.35	β = 90
c = 82.37	γ = 120

Software Package:

Software Name	Purpose
REFMAC	refinement
DENZO	data reduction
SCALEPACK	data scaling
AMoRE	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2001-01-28

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2001-01-28
Type: Initial release
Version 1.1: 2011-07-13
Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
Version 1.2: 2012-11-30
Changes: Other
Version 1.3: 2019-05-08
Changes: Data collection, Derived calculations, Experimental preparation, Other
Version 1.4: 2019-10-09
Changes: Data collection, Other
Version 1.5: 2023-12-06
Changes: Data collection, Database references, Derived calculations, Refinement description