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- PDB-4nwl: Crystal structure of hepatis c virus protease (ns3) complexed wit... -

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Basic information

Entry
Database: PDB / ID: 4nwl
TitleCrystal structure of hepatis c virus protease (ns3) complexed with bms-650032 aka n-(tert-butoxycarbonyl)-3-me thyl-l-valyl-(4r)-4-((7-chloro-4-methoxy-1-isoquinolinyl)o xy)-n-((1r,2s)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylc yclopropyl)-l-prolinamide
ComponentsHCV NS3 1a Protease
KeywordsHYDROLASE/HYDROLASE INHIBITOR / SERINE PROTEASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / 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 / lipid droplet / ribonucleoside triphosphate phosphatase activity / channel activity ...host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / 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 / lipid droplet / ribonucleoside triphosphate phosphatase activity / channel activity / monoatomic ion transmembrane transport / viral nucleocapsid / clathrin-dependent endocytosis of virus by host cell / RNA helicase activity / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / ribonucleoprotein complex / viral RNA genome replication / cysteine-type endopeptidase activity / serine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / viral envelope / host cell nucleus / virion attachment to host cell / apoptotic process / host cell plasma membrane / structural molecule activity / virion membrane / proteolysis / RNA binding / zinc ion binding / ATP binding / plasma membrane / cytoplasm
Similarity search - Function
Thrombin, subunit H - #120 / Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / 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 NS2, C-terminal domain / Hepatitis C virus core protein, chain A superfamily ...Thrombin, subunit H - #120 / Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / 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 NS2, C-terminal domain / Hepatitis C virus core protein, chain A superfamily / : / Hepatitis C virus non-structural protein NS4b / Hepatitis C virus capsid protein / 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 zinc finger domain / Hepatitis C virus non-structural 5a domain 1b / Hepatitis C virus, Non-structural protein NS2 / : / NS3 RNA helicase, C-terminal helical domain / Hepacivirus nonstructural protein 2 (NS2) protease domain profile. / Hepatitis C virus non-structural 5a protein membrane anchor / 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 / Hepacivirus/Pegivirus NS3 protease domain profile. / Hepatitis C virus NS3 protease / DEAD box, Flavivirus / Flavivirus DEAD domain / helicase superfamily c-terminal domain / Trypsin-like serine proteases / 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 / 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-2R9 / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsMuckelbauer, J.K. / Klei, H.E.
Citation
Journal: J.Med.Chem. / Year: 2014
Title: Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.
Authors: Scola, P.M. / Wang, A.X. / Good, A.C. / Sun, L.Q. / Combrink, K.D. / Campbell, J.A. / Chen, J. / Tu, Y. / Sin, N. / Venables, B.L. / Sit, S.Y. / Chen, Y. / Cocuzza, A. / Bilder, D.M. / ...Authors: Scola, P.M. / Wang, A.X. / Good, A.C. / Sun, L.Q. / Combrink, K.D. / Campbell, J.A. / Chen, J. / Tu, Y. / Sin, N. / Venables, B.L. / Sit, S.Y. / Chen, Y. / Cocuzza, A. / Bilder, D.M. / D'Andrea, S. / Zheng, B. / Hewawasam, P. / Ding, M. / Thuring, J. / Li, J. / Hernandez, D. / Yu, F. / Falk, P. / Zhai, G. / Sheaffer, A.K. / Chen, C. / Lee, M.S. / Barry, D. / Knipe, J.O. / Li, W. / Han, Y.H. / Jenkins, S. / Gesenberg, C. / Gao, Q. / Sinz, M.W. / Santone, K.S. / Zvyaga, T. / Rajamani, R. / Klei, H.E. / Colonno, R.J. / Grasela, D.M. / Hughes, E. / Chien, C. / Adams, S. / Levesque, P.C. / Li, D. / Zhu, J. / Meanwell, N.A. / McPhee, F.
#1: Journal: CRYST.GROWTH DES. / Year: 2011
Title: Image annotation and database mining to create a novel screen for the chemotype-dependent crystallization of HCV NS3 protease
Authors: Klei, H.E. / Kish, K. / Russo, M.F. / Michalczyk, S.J. / Cahn, M.H. / Tredup, J. / Chang, C. / Khan, J. / Baldwin, E.T.
History
DepositionDec 6, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 26, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 25, 2015Group: Non-polymer description
Revision 1.2Aug 9, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / 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_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_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.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_label_asym_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

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Assembly

Deposited unit
A: HCV NS3 1a Protease
B: HCV NS3 1a Protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,1506
Polymers46,5232
Non-polymers1,6274
Water2,018112
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A: HCV NS3 1a Protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,0753
Polymers23,2611
Non-polymers8142
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: HCV NS3 1a Protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,0753
Polymers23,2611
Non-polymers8142
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.412, 67.761, 61.307
Angle α, β, γ (deg.)90.000, 108.460, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein HCV NS3 1a Protease


Mass: 23261.316 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: The protein crystallized is a single-chain construct of protease domain of hepatitis C virus NS3/4A, with cofactor 4A covalently linked at the N-terminus.
Source: (gene. exp.) Hepatitis C virus / Strain: 1a / Production host: Escherichia coli (E. coli) / References: UniProt: A8DG50
#2: Chemical ChemComp-2R9 / N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-[(7-chloro-4-methoxyisoquinolin-1-yl)oxy]-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-L-prolinamide / Asunaprevir


Mass: 748.286 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C35H46ClN5O9S / Comment: inhibitor*YM
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 112 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsThe cofactor 4A residues -10-0(GLY SER VAL VAL ILE VAL GLY ARG ILE ASN LEU) in this entry ...The cofactor 4A residues -10-0(GLY SER VAL VAL ILE VAL GLY ARG ILE ASN LEU) in this entry correspond to residues numbering 1678-1688 of database sequence reference (UNP A8DG50). This peptide is covalently linked to the N-terminus of NS3 via LINKER (SER GLY ASP THR). C1679S mutation was engineered to prevent disulfide formation. The V1686I and I1687N were engineered to optimize the linker between the cofactor 4A and NS3.

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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: 1.92 Å3/Da / Density % sol: 36.04 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.54 / Wavelength: 1.541 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jun 1, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
11.541
21.5411
ReflectionResolution: 2.2→50 Å / Num. obs: 17859 / % possible obs: 99.4 % / Observed criterion σ(I): 0 / Redundancy: 3.5 % / Biso Wilson estimate: 27 Å2 / Rmerge(I) obs: 0.093 / Χ2: 1.055 / Net I/σ(I): 12.3
Reflection shellResolution: 2.2→4.74 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.06 / Mean I/σ(I) obs: 17.7 / Num. unique all: 1847 / Χ2: 1.051 / % possible all: 99.8

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
CNX2005refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→36.35 Å / Rfactor Rfree error: 0.012 / Occupancy max: 1 / Occupancy min: 1 / Data cutoff high absF: 1162918 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.289 623 3.5 %RANDOM
Rwork0.246 ---
obs0.248 17845 99 %-
all-17845 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 40.6814 Å2 / ksol: 0.3795 e/Å3
Displacement parametersBiso max: 60.42 Å2 / Biso mean: 22.2232 Å2 / Biso min: 5.31 Å2
Baniso -1Baniso -2Baniso -3
1-8.28 Å20 Å22.41 Å2
2---2.86 Å20 Å2
3----5.42 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.4 Å0.3 Å
Luzzati d res low-5 Å
Luzzati sigma a0.41 Å0.23 Å
Refinement stepCycle: LAST / Resolution: 2.2→36.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2876 0 104 112 3092
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.012
X-RAY DIFFRACTIONc_angle_deg3.1
X-RAY DIFFRACTIONc_dihedral_angle_d22.2
X-RAY DIFFRACTIONc_improper_angle_d2.52
X-RAY DIFFRACTIONc_mcbond_it2.481.5
X-RAY DIFFRACTIONc_mcangle_it3.012
X-RAY DIFFRACTIONc_scbond_it2.762
X-RAY DIFFRACTIONc_scangle_it3.392.5
LS refinement shellResolution: 2.2→2.3 Å / Rfactor Rfree error: 0.049 / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.407 69 3.3 %
Rwork0.292 2053 -
all-2122 -
obs--95.2 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAPROTEIN.TOP
X-RAY DIFFRACTION2DNA-RNA_REP.PARAWATER.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMION.TOP
X-RAY DIFFRACTION4ION.PARAMLIGAND.TOP
X-RAY DIFFRACTION5LIGAND.PARAM

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