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- PDB-2a4r: HCV NS3 Protease Domain with a Ketoamide Inhibitor Covalently bound. -

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Basic information

Entry
Database: PDB / ID: 2a4r
TitleHCV NS3 Protease Domain with a Ketoamide Inhibitor Covalently bound.
Components
  • NS3 protease/helicase
  • Ns4a peptide
KeywordsVIRAL PROTEIN
Function / homology
Function and homology information


positive regulation of hexokinase activity / modulation by virus of host cellular process / translocation of peptides or proteins into host cell cytoplasm / Toll-like receptor 2 binding / self proteolysis / viral capsid assembly / adhesion receptor-mediated virion attachment to host cell / TBC/RABGAPs / hepacivirin / host cell mitochondrial membrane ...positive regulation of hexokinase activity / modulation by virus of host cellular process / translocation of peptides or proteins into host cell cytoplasm / Toll-like receptor 2 binding / self proteolysis / viral capsid assembly / adhesion receptor-mediated virion attachment to host cell / TBC/RABGAPs / hepacivirin / host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / positive regulation of cytokinesis / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / negative regulation of protein secretion / host cell membrane / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / endoplasmic reticulum-Golgi intermediate compartment membrane / viral process / serine-type peptidase activity / virion component / SH3 domain binding / kinase binding / : / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / clathrin-dependent endocytosis of virus by host cell / viral nucleocapsid / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / entry receptor-mediated virion attachment to host cell / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / RNA helicase / induction by virus of host autophagy / ribonucleoprotein complex / symbiont entry into host cell / RNA-directed RNA polymerase / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / host cell nucleus / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / negative regulation of transcription by RNA polymerase II / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane / metal ion binding
Similarity search - Function
Thrombin, subunit H - #120 / Hepatitis C virus core protein, chain A superfamily / Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / Hepatitis C virus non-structural protein NS2, C-terminal domain / Hepatitis C virus non-structural protein NS2, N-terminal domain / Hepatitis C virus non-structural protein NS2 / HCV NS5a protein C-terminal region / Hepatitis C virus, Non-structural protein NS4b / Hepatitis C virus, Core protein, N-terminal ...Thrombin, subunit H - #120 / Hepatitis C virus core protein, chain A superfamily / Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / Hepatitis C virus non-structural protein NS2, C-terminal domain / Hepatitis C virus non-structural protein NS2, N-terminal domain / Hepatitis C virus non-structural protein NS2 / HCV NS5a protein C-terminal region / Hepatitis C virus, Non-structural protein NS4b / Hepatitis C virus, Core protein, N-terminal / Hepatitis C virus non-structural protein NS4b / Hepatitis C virus capsid protein / Hepatitis C virus, Non-structural protein NS2 / Hepatitis C virus, Non-structural 5a protein / Hepatitis C virus, Non-structural 5a protein, domain 1a / Hepatitis C virus non-structural 5a, 1B domain / NS5A domain 1a superfamily / Hepatitis C virus non-structural 5a protein membrane anchor / Hepatitis C virus non-structural 5a zinc finger domain / Hepatitis C virus non-structural 5a domain 1b / Hepacivirus nonstructural protein 2 (NS2) protease domain profile. / Hepatitis C virus, Non-structural protein NS4a / Hepatitis C virus non-structural protein NS4a / Hepatitis C virus, Core protein, C-terminal / Hepatitis C virus core protein / Hepatitis C virus, Non-structural protein E2/NS1 / Hepatitis C virus non-structural protein E2/NS1 / Hepatitis C virus, Envelope glycoprotein E1 / Hepatitis C virus envelope glycoprotein E1 / RNA dependent RNA polymerase, hepatitis C virus / Viral RNA dependent RNA polymerase / Hepatitis C virus, NS3 protease, Peptidase S29 / Hepatitis C virus NS3 protease / Hepacivirus/Pegivirus NS3 protease domain profile. / DEAD box, Flavivirus / Flavivirus DEAD domain / helicase superfamily c-terminal domain / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / Trypsin-like serine proteases / Thrombin, subunit H / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / Beta Barrel / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Chem-BNH / Non-structural protein 4a/b / Genome polyprotein / NS3 protease
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.4 Å
AuthorsBogen, S. / Saksena, A.K. / Arasappan, A. / Gu, H. / Njoroge, F.G. / Girijavallabhan, V. / Pichardo, J. / Butkiewicz, N. / Prongay, A. / Madison, V.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2005
Title: Hepatitis C Virus NS3-4A serine protease inhibitors: Use of a P2-P1 cyclopropyl alanine combination for improved potency.
Authors: Bogen, S. / Saksena, A.K. / Arasappan, A. / Gu, H. / Njoroge, F.G. / Girijavallabhan, V. / Pichardo, J. / Butkiewicz, N. / Prongay, A. / Madison, V.
#1: Journal: Cell(Cambridge,Mass.) / Year: 1996
Title: Crystal Structure of the Hepatitis C Virus NS3 Protease Domain Complexed with a Synthetic NS4a Cofactor Peptide
Authors: Kim, J.L. / Morgenstern, K.A. / Lin, C. / Fox, T. / Dwyer, M.D. / Landro, J.A. / Chambers, S.P. / Markland, W. / Lepre, C.A. / O'Malley, E.T. / Harbeson, S.L. / Rice, C.M. / Murcko, M.A. / ...Authors: Kim, J.L. / Morgenstern, K.A. / Lin, C. / Fox, T. / Dwyer, M.D. / Landro, J.A. / Chambers, S.P. / Markland, W. / Lepre, C.A. / O'Malley, E.T. / Harbeson, S.L. / Rice, C.M. / Murcko, M.A. / Caron, P.R. / Thomson, J.A.
#2: Journal: Bioorg.Med.Chem.Lett. / Year: 2005
Title: Hepatitis C virus NS3-4A serine protease inhibitors. SAR of P2' moiety with improved potency.
Authors: Arasappan, A. / Njoroge, F.G. / Chan, T.Y. / Bennett, F. / Bogen, S.L. / Chen, K. / Gu, H. / Hong, L. / Jao, E. / Liu, Y.T. / Lovey, R.G. / Parekh, T. / Pike, R.E. / Pinto, P. / Santhanam, B. ...Authors: Arasappan, A. / Njoroge, F.G. / Chan, T.Y. / Bennett, F. / Bogen, S.L. / Chen, K. / Gu, H. / Hong, L. / Jao, E. / Liu, Y.T. / Lovey, R.G. / Parekh, T. / Pike, R.E. / Pinto, P. / Santhanam, B. / Venkatraman, S. / Vaccaro, H. / Wang, H. / Yang, X. / Zhu, Z. / Mckittrick, B. / Saksena, A.K. / Girijavallabhan, V. / Pichardo, J. / Butkiewicz, N. / Ingram, R. / Malcolm, B. / Prongay, A.J. / Yao, N. / Marten, B. / Madison, V. / Kemp, S. / Levy, O. / Lim-Wilby, M. / Tamura, S. / Ganguly, A.K.
#3: Journal: Cell(Cambridge,Mass.) / Year: 1996
Title: The Crystal Structure of Hepatitis C Virus NS3 proteinase Reveals a Trypsin-like fold and a Structural Zinc Binding Site.
Authors: Love, R.A. / Parge, H.E. / Wickersham, J.A. / Hostomsky, Z. / Habuka, N. / Moomaw, E.W. / Adachi, T. / Hostomska, Z.
#4: Journal: Protein Sci. / Year: 1998
Title: Complex of NS3 protease and NS4a peptide of BK strain hepatitis C virus: A 2.2A resolution structure in a hexagonal crystal form.
Authors: Yan, Y. / Li, Y. / Munshi, S. / Sardana, V. / Cole, J.L. / Sardana, M. / Steinkuehler, C. / Tomei, L. / De Francesco, R. / Kuo, L.C. / Chen, Z.
#5: Journal: J.Biol.Chem. / Year: 2000
Title: Inhibition of the Hepatitis C Virus NS3/4A Protease. The Crystal Structures of Two protease-inhibitor complexes.
Authors: DiMarco, S. / Rizzi, M. / Volpari, C. / Walsh, M.A. / Narjes, F. / Colarusso, S. / De Francesco, R. / Matassa, V.G. / Sollazzo, M.
History
DepositionJun 29, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 4, 2006Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 20, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Feb 14, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: NS3 protease/helicase
B: Ns4a peptide
C: NS3 protease/helicase
D: Ns4a peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,0837
Polymers47,2554
Non-polymers8293
Water2,900161
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7660 Å2
ΔGint-126 kcal/mol
Surface area15420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)223.603, 223.603, 75.354
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32

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Components

#1: Protein NS3 protease/helicase


Mass: 21233.225 Da / Num. of mol.: 2 / Fragment: protease domain, residues 1-181
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Genus: Hepacivirus / Production host: Escherichia coli (E. coli) / References: UniProt: Q91RS4, UniProt: P27958*PLUS
#2: Protein/peptide Ns4a peptide


Mass: 2394.039 Da / Num. of mol.: 2 / Fragment: residues 21-39 / Source method: obtained synthetically
Details: THE PEPTIDE WAS CHEMICALLY SYNTHESIZED. THE SEQUENCE OF THE PROTEIN IS NATURALLY FOUND IN HEPATITIS C VIRUS TYPE 1B.
References: UniProt: O39914, UniProt: P27958*PLUS
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-BNH / [(N-{3-[(N-{CYCLOHEXYL[(ISOBUTOXYCARBONYL)AMINO]ACETYL}-3-CYCLOPROPYLALANYL)AMINO]-4-CYCLOPROPYL-2-OXOBUTANOYL}GLYCYL)AMINO](PHENYL)ACETIC ACID


Mass: 697.818 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H51N5O9
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 161 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal
IDDensity Matthews (Å3/Da)Density % sol (%)
13.8467.94
2
Crystal grow
Temperature (K)Crystal-IDMethodpHDetails
2731vapor diffusion, hanging drop5.7MES, sodium potassium phosphate, sodium chloride, 2-mercaptoethanol, pH 5.7, VAPOR DIFFUSION, HANGING DROP, temperature 273K
2852vapor diffusion, hanging drop5.7MES, sodium potassium phosphate, sodium chloride, 2-mercaptoethanol, pH 5.7, VAPOR DIFFUSION, HANGING DROP, temperature 285K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Apr 8, 1999
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.4→100 Å / Num. all: 28197 / Num. obs: 28197 / % possible obs: 99.2 % / Observed criterion σ(I): 2.4 / Redundancy: 3.5 % / Rmerge(I) obs: 0.047 / Net I/σ(I): 23.3
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.489 / Mean I/σ(I) obs: 24 / Num. unique all: 2777 / % possible all: 98.8

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
X-PLORmodel building
X-PLOR98.1refinement
X-PLORphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.4→8 Å / Isotropic thermal model: ISOTROPIC / Cross valid method: THROUGHOUT / σ(I): 2.36 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.271 2540 -RANDOM
Rwork0.201 ---
all0.206 25500 --
obs-25500 9.96 %-
Refinement stepCycle: LAST / Resolution: 2.4→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2724 0 52 161 2937
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.009
X-RAY DIFFRACTIONx_angle_deg1.81
X-RAY DIFFRACTIONx_improper_angle_d1.237
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkRefine-IDNum. reflection obs
2.4-2.510.35425630.308X-RAY DIFFRACTION5645
2.63-30.3076470.267X-RAY DIFFRACTION6289
3-3.710.2696660.208X-RAY DIFFRACTION6701
3.71-80.2296640.162X-RAY DIFFRACTION6865

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