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- PDB-6n4n: Crystal structure of the designed protein DNCR2/danoprevir/NS3a c... -

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Basic information

Entry
Database: PDB / ID: 6n4n
TitleCrystal structure of the designed protein DNCR2/danoprevir/NS3a complex
Components
  • NS3 protease
  • Rosetta-designed danoprevir/NS3a complex reader 2
KeywordsDE NOVO PROTEIN/HYDROLASE/INHIBITOR / Rosetta design / PROCISiR / NS3a / danoprevir / DE NOVO PROTEIN-HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


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 / serine-type peptidase activity ...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 / serine-type peptidase activity / virion component / SH3 domain 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 / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / RNA helicase / induction by virus of host autophagy / RNA-directed RNA polymerase / symbiont entry into host cell / ribonucleoprotein complex / 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 / structural molecule activity / virion attachment to host cell / host cell plasma membrane / 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 / 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 / DNA/RNA polymerase superfamily / Peptidase S1, PA clan / Beta Barrel / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Chem-TSV / NS3 protease / Genome polyprotein
Similarity search - Component
Biological speciesHepacivirus C
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.29 Å
AuthorsWang, Z. / Foight, G.W. / Baker, D. / Maly, D.J.
CitationJournal: Nat.Biotechnol. / Year: 2019
Title: Multi-input chemical control of protein dimerization for programming graded cellular responses.
Authors: Foight, G.W. / Wang, Z. / Wei, C.T. / Jr Greisen, P. / Warner, K.M. / Cunningham-Bryant, D. / Park, K. / Brunette, T.J. / Sheffler, W. / Baker, D. / Maly, D.J.
History
DepositionNov 19, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 11, 2019Provider: repository / Type: Initial release
Revision 1.1Sep 25, 2019Group: Data collection / Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 16, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_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: Rosetta-designed danoprevir/NS3a complex reader 2
F: Rosetta-designed danoprevir/NS3a complex reader 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,35714
Polymers93,1904
Non-polymers2,16710
Water3,765209
1
A: NS3 protease
F: Rosetta-designed danoprevir/NS3a complex reader 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,6787
Polymers46,5952
Non-polymers1,0835
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: NS3 protease
C: Rosetta-designed danoprevir/NS3a complex reader 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,6787
Polymers46,5952
Non-polymers1,0835
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)70.840, 69.256, 99.344
Angle α, β, γ (deg.)90.000, 108.590, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12C
22F

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LYSLYSPROPROAA988 - 11823 - 197
21LYSLYSPROPROBB988 - 11823 - 197
12SERSERGLUGLUCC1 - 1912 - 192
22SERSERGLUGLUFD1 - 1912 - 192

NCS ensembles :
ID
1
2

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Components

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Protein , 2 types, 4 molecules ABCF

#1: Protein NS3 protease / protease NS3a


Mass: 20915.699 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepacivirus C / Production host: Escherichia coli (E. coli)
References: UniProt: A0A0B4WYC6, UniProt: P26664*PLUS, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#2: Protein Rosetta-designed danoprevir/NS3a complex reader 2 / DNCR2


Mass: 25679.264 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)

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Non-polymers , 4 types, 219 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-TSV / (2R,6S,12Z,13aS,14aR,16aS)-6-[(tert-butoxycarbonyl)amino]-14a-[(cyclopropylsulfonyl)carbamoyl]-5,16-dioxo-1,2,3,5,6,7,8 ,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl 4-fluoro-2H-isoindole-2-carboxylate / ITMN-191 / danoprevir / Danoprevir


Mass: 729.815 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C35H44FN5O9S / Feature type: SUBJECT OF INVESTIGATION / Comment: inhibitor*YM
#5: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 18.015 Da / Num. of mol.: 209 / 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: 2.48 Å3/Da / Density % sol: 50.38 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop
Details: 100 mM Bis-Tris, pH 6.5, 200 mM lithium sulfate, 22% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 16, 2017
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.29→94.16 Å / Num. obs: 38559 / % possible obs: 99.3 % / Redundancy: 4.1 % / Rmerge(I) obs: 0.102 / Net I/σ(I): 14.4
Reflection shellResolution: 2.3→2.37 Å / Rmerge(I) obs: 0.34 / Num. unique obs: 3179

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.8.0189refinement
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3M5L

3m5l


Resolution: 2.29→94.16 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.923 / SU B: 12.217 / SU ML: 0.159 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.317 / ESU R Free: 0.226
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2408 1979 4.9 %RANDOM
Rwork0.2035 ---
obs0.2053 38559 98.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 149.82 Å2 / Biso mean: 45.699 Å2 / Biso min: 17.08 Å2
Baniso -1Baniso -2Baniso -3
1-1.91 Å20 Å20.48 Å2
2---1.19 Å20 Å2
3----0.85 Å2
Refinement stepCycle: final / Resolution: 2.29→94.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5818 0 134 209 6161
Biso mean--34.95 36.88 -
Num. residues----765
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0196030
X-RAY DIFFRACTIONr_angle_refined_deg1.4612.0018192
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5335760
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.37823.623276
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.223151015
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2331570
X-RAY DIFFRACTIONr_chiral_restr0.0860.2951
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214566
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A113960.06
12B113960.06
21C112120.07
22F112120.07
LS refinement shellResolution: 2.291→2.351 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.29 119 -
Rwork0.269 2299 -
all-2418 -
obs--80.49 %
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)
11.10340.3335-0.53211.0322-0.19430.6777-0.0272-0.0458-0.0606-0.0872-0.0827-0.09870.00990.00170.10990.05990.0198-0.02880.04280.01840.0655-5.6803-9.603432.47
20.29030.07830.30620.9542-0.39661.1840.0573-0.0068-0.05710.0748-0.0811-0.0056-0.16610.05060.02370.1371-0.0104-0.04120.01140.00590.0264-0.645320.990217.7571
31.5589-1.2080.84091.957-0.21461.3422-0.0265-0.1060.0099-0.2891-0.12040.1185-0.0825-0.16970.1470.19710.0634-0.08890.0484-0.03050.0619-18.874613.1293-4.3942
41.98770.65730.43540.93980.42151.19260.13380.0114-0.0942-0.0432-0.19170.19170.0377-0.05830.05790.03810.0327-0.06840.0562-0.07680.1462-33.7578-0.862437.756
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A988 - 1182
2X-RAY DIFFRACTION2B988 - 1182
3X-RAY DIFFRACTION3C1 - 191
4X-RAY DIFFRACTION4F1 - 191

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