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- PDB-2a4q: HCV NS3 protease with NS4a peptide and a covalently bound macrocy... -

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Basic information

Entry
Database: PDB / ID: 2a4q
TitleHCV NS3 protease with NS4a peptide and a covalently bound macrocyclic ketoamide compound.
Components
  • NS3 protease/helicase'
  • NS4a peptide
KeywordsVIRAL PROTEIN
Function / homology
Function and homology information


self proteolysis / symbiont-mediated transformation of host cell / host cell membrane / viral process / serine-type peptidase activity / virion component / host cell / symbiont entry into host cell / virion attachment to host cell / virion membrane ...self proteolysis / symbiont-mediated transformation of host cell / host cell membrane / viral process / serine-type peptidase activity / virion component / host cell / symbiont entry into host cell / virion attachment to host cell / virion membrane / membrane / metal ion binding
Similarity search - Function
Thrombin, subunit H - #120 / Hepatitis C virus, Non-structural protein NS4a / Hepatitis C virus non-structural protein NS4a / Hepatitis C virus, NS3 protease, Peptidase S29 / Hepatitis C virus NS3 protease / Hepacivirus/Pegivirus NS3 protease domain profile. / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
BETA-MERCAPTOETHANOL / Chem-FNH / Non-structural protein 4a/b / NS3 protease
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.45 Å
AuthorsChen, K.X. / Njoroge, F.G. / Prongay, A. / Pichardo, J. / Madison, V. / Girijavallabhan, V.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2005
Title: Synthesis and Biological Activity of Macrocyclic Inhibitors of Hepatitis C Virus (HCV) NS3 Protease
Authors: Chen, K.X. / Njoroge, F.G. / Prongay, A. / Pichardo, J. / Madison, V. / Girijavallabhan, 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, L.J. / 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 / pdbx_struct_conn_angle ...database_2 / pdbx_struct_conn_angle / 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 / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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_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_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)48,2098
Polymers47,2554
Non-polymers9554
Water3,045169
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7970 Å2
ΔGint-130 kcal/mol
Surface area15390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)224.923, 224.923, 75.317
Angle α, β, γ (deg.)90, 90, 120
Int Tables number155
Space group name H-MH32
DetailsDimer (Chains A and C) of the protease domain with a NS4a peptide bound (Chains B and D). Only Chain A has the covalent adducts with the inhibitor SCH383913 and 2-mercaptoethanol.

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ACBD

#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
#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

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Non-polymers , 4 types, 173 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-BME / BETA-MERCAPTOETHANOL


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS
#5: Chemical ChemComp-FNH / (2R)-({N-[(3S)-3-({[(3S,6S)-6-CYCLOHEXYL-5,8-DIOXO-4,7-DIAZABICYCLO[14.3.1]ICOSA-1(20),16,18-TRIEN-3-YL]CARBONYL}AMINO)-2-OXOHEXANOYL]GLYCYL}AMINO)(PHENYL)ACETIC ACID


Mass: 745.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C41H55N5O8
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 169 / 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

CrystalDensity Matthews: 3.88 Å3/Da / Density % sol: 68.28 %
Crystal growTemperature: 285 K / Method: vapor diffusion, hanging drop / pH: 5.7
Details: MES, sodium potassium phosphate, sodium chloride, 2-mercaptoethanol, pH 5.7, VAPOR DIFFUSION, HANGING DROP, temperature 285K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Nov 15, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.45→50 Å / Num. obs: 26060 / % possible obs: 98.63 % / Observed criterion σ(I): 1.7 / Redundancy: 3.8 % / Rmerge(I) obs: 0.071 / Net I/σ(I): 15.36
Reflection shellResolution: 2.45→2.51 Å / Rmerge(I) obs: 0.466 / Mean I/σ(I) obs: 1.72 / Num. unique all: 1580 / % possible all: 89.2

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
X-PLORmodel building
X-PLOR98.1refinement
HKL-2000data reduction
X-PLORphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.45→8 Å / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.274 2022 -RANDOM
Rwork0.191 ---
obs-20478 9.87 %-
Refinement stepCycle: LAST / Resolution: 2.45→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2724 0 60 169 2953
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.009
X-RAY DIFFRACTIONx_angle_deg1.845
X-RAY DIFFRACTIONx_improper_angle_d1.331
LS refinement shellResolution: 2.45→2.51 Å
RfactorNum. reflection% reflection
Rfree0.2569 550 -
Rwork0.1533 --
obs-5593 76.98 %

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