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- PDB-4k8b: Crystal structure of HCV NS3/4A protease complexed with inhibitor -

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Basic information

Entry
Database: PDB / ID: 4k8b
TitleCrystal structure of HCV NS3/4A protease complexed with inhibitor
Components
  • NS3 protease
  • Nonstructural protein
KeywordsHYDROLASE/HYDROLASE INHIBITOR / protease / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


virion component => GO:0044423 / hepacivirin / 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 / 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 ...virion component => GO:0044423 / hepacivirin / 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 / 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 / viral process / serine-type peptidase activity / virion component / SH3 domain binding / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / viral nucleocapsid / clathrin-dependent endocytosis of virus by host cell / membrane => GO:0016020 / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / 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 / RNA helicase / ribonucleoprotein complex / symbiont entry into host cell / induction by virus of host autophagy / RNA-directed RNA polymerase / 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 / host cell plasma membrane / structural molecule activity / virion membrane / 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 ...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 / 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
N-(TERT-BUTYLCARBAMOYL)-3-METHYL-L-VALYL-(4R)-N-[(1R,2S)-1-CARBOXY-2-ETHENYLCYCLOPROPYL]-4-[(7-METHOXY-2-PHENYLQUINOLIN-4-YL)OXY]-L-PROLINAMIDE / Chem-1RR / Genome polyprotein / NS3 protease / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsNar, H.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Ligand bioactive conformation plays a critical role in the design of drugs that target the hepatitis C virus NS3 protease.
Authors: Laplante, S.R. / Nar, H. / Lemke, C.T. / Jakalian, A. / Aubry, N. / Kawai, S.H.
History
DepositionApr 18, 2013Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Mar 26, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_source / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_source.pdbx_synchrotron_site / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_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_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_label_asym_id / _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
B: NS3 protease
C: Nonstructural protein
D: Nonstructural protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,40712
Polymers40,5204
Non-polymers1,8878
Water1,62190
1
A: NS3 protease
C: Nonstructural protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,2046
Polymers20,2602
Non-polymers9434
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2620 Å2
ΔGint-35 kcal/mol
Surface area8550 Å2
MethodPISA
2
B: NS3 protease
D: Nonstructural protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,2046
Polymers20,2602
Non-polymers9434
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2760 Å2
ΔGint-72 kcal/mol
Surface area8610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.182, 76.182, 169.206
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

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

#1: Protein NS3 protease


Mass: 19046.730 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Production host: Escherichia coli (E. coli) / References: UniProt: Q0ZNA6, hepacivirin
#2: Protein/peptide Nonstructural protein / non-structural protein 4A


Mass: 1213.492 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 107-118
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus / Gene: NS3-NS4 / Production host: Escherichia coli (E. coli) / References: UniProt: Q81584, UniProt: P26663*PLUS

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Non-polymers , 4 types, 98 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-1RR / N-(tert-butylcarbamoyl)-3-methyl-L-valyl-(4R)-N-[(1R,2S)-1-carboxy-2-ethenylcyclopropyl]-4-[(7-methoxy-2-phenylquinolin-4-yl)oxy]-L-prolinamide


Type: Peptide-like / Class: Enzyme inhibitor / Mass: 685.809 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C38H47N5O7
References: N-(TERT-BUTYLCARBAMOYL)-3-METHYL-L-VALYL-(4R)-N-[(1R,2S)-1-CARBOXY-2-ETHENYLCYCLOPROPYL]-4-[(7-METHOXY-2-PHENYLQUINOLIN-4-YL)OXY]-L-PROLINAMIDE
#5: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 90 / 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: 3.5 Å3/Da / Density % sol: 64.84 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 2.0M ammonium sulfate, 0.2M sodium phosphate, pH 5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: EMBL/DESY, HAMBURG / Beamline: BW7B / Wavelength: 1.05 Å
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Aug 3, 1999
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.05 Å / Relative weight: 1
ReflectionResolution: 2.8→100 Å / Num. obs: 15366 / % possible obs: 99.7 % / Observed criterion σ(F): 2 / Biso Wilson estimate: 64.49 Å2 / Rmerge(I) obs: 0.053
Reflection shellResolution: 2.8→2.9 Å / % possible all: 100

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Processing

Software
NameVersionClassification
AMoREphasing
BUSTER2.11.4refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1JXP

1jxp


Resolution: 2.8→18.93 Å / Cor.coef. Fo:Fc: 0.8908 / Cor.coef. Fo:Fc free: 0.8798 / SU R Cruickshank DPI: 0.604 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2318 732 5.03 %RANDOM
Rwork0.2027 ---
obs0.2042 14558 99.92 %-
all-15366 --
Displacement parametersBiso mean: 69.92 Å2
Baniso -1Baniso -2Baniso -3
1--10.2436 Å20 Å20 Å2
2---10.2436 Å20 Å2
3---20.4872 Å2
Refine analyzeLuzzati coordinate error obs: 0.501 Å
Refinement stepCycle: LAST / Resolution: 2.8→18.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2772 0 122 90 2984
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082946HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.174030HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d990SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes48HARMONIC2
X-RAY DIFFRACTIONt_gen_planes494HARMONIC5
X-RAY DIFFRACTIONt_it2946HARMONIC20
X-RAY DIFFRACTIONt_nbd3SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.9
X-RAY DIFFRACTIONt_other_torsion20.22
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion396SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3407SEMIHARMONIC4
LS refinement shellResolution: 2.8→3.02 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.2766 154 5.2 %
Rwork0.2199 2806 -
all0.2226 2960 -
obs--99.92 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.44941.0481-0.55742.9421-0.55735.12990.2382-0.1058-0.2460.3587-0.54980.01220.5394-0.47030.3116-0.2176-0.32530.0860.2839-0.1695-0.093426.666449.099649.2932
25.07160.16711.11923.20260.76073.8241-0.20440.40030.32360.5568-0.39250.18770.1959-0.87340.5969-0.1454-0.44970.06740.2332-0.1634-0.178716.966671.458370.049
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|3 - A|179 A|201 - A|201 }A3 - 179
2X-RAY DIFFRACTION1{ A|3 - A|179 A|201 - A|201 }A201
3X-RAY DIFFRACTION2{ B|3 - B|179 B|201 - B|201 }B3 - 179
4X-RAY DIFFRACTION2{ B|3 - B|179 B|201 - B|201 }B201

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