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- PDB-6vgz: 2.25 A resolution structure of MERS 3CL protease in complex with ... -

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Basic information

Entry
Database: PDB / ID: 6vgz
Title2.25 A resolution structure of MERS 3CL protease in complex with inhibitor 6d
ComponentsOrf1a protein
KeywordsHYDROLASE/HYDROLASE Inhibitor / PROTEASE / MERS 3CL protease Inhhibitors / HYDROLASE / HYDROLASE-HYDROLASE Inhibitor complex
Function / homology
Function and homology information


host cell membrane / viral genome replication / methyltransferase activity / host cell endoplasmic reticulum-Golgi intermediate compartment / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / endonuclease activity / symbiont-mediated degradation of host mRNA / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding ...host cell membrane / viral genome replication / methyltransferase activity / host cell endoplasmic reticulum-Golgi intermediate compartment / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / endonuclease activity / symbiont-mediated degradation of host mRNA / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / methylation / omega peptidase activity / symbiont-mediated suppression of host NF-kappaB cascade / symbiont-mediated perturbation of host ubiquitin-like protein modification / methyltransferase cap1 activity / cysteine-type deubiquitinase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / single-stranded RNA binding / regulation of autophagy / host cell perinuclear region of cytoplasm / viral protein processing / lyase activity / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / viral translational frameshifting / symbiont-mediated activation of host autophagy / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / proteolysis / zinc ion binding / ATP binding / membrane
Similarity search - Function
RNA-dependent RNA polymerase, Middle East respiratory syndrome-related coronavirus / Non-structural protein 2, MERS-CoV-like / NSP3, SUD-C domain, MERS-CoV-like / AAA domain / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / Nonstructural protein 14, betacoronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus ...RNA-dependent RNA polymerase, Middle East respiratory syndrome-related coronavirus / Non-structural protein 2, MERS-CoV-like / NSP3, SUD-C domain, MERS-CoV-like / AAA domain / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / Nonstructural protein 14, betacoronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / : / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Coronavirus Nsp12 Interface domain profile. / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Nidovirus 2-O-methyltransferase / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, N-terminal oligomerization / Nonstructural protein 15, middle domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 3'-5' exoribonuclease domain / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Endoribonuclease EndoU-like / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / : / DNA2/NAM7 helicase-like, C-terminal / AAA domain / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Trypsin-like serine proteases / Betacoronavirus Nsp3c-M domain profile. / NSP1, globular domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Betacoronavirus replicase NSP1 / Betacoronavirus single-stranded poly(A) binding domain / NSP1, C-terminal domain, betacoronavirus / : / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / Betacoronavirus Nsp3c-C domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Non-structural protein NSP3, nucleic acid-binding domain superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Papain-like viral protease, palm and finger domains, coronavirus / Papain-like protease, N-terminal domain superfamily, coronavirus / Coronavirus replicase NSP2, N-terminal / : / Coronavirus replicase NSP2, C-terminal / Coronavirus (CoV) Nsp2 middle domain profile. / NSP1, globular domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / Nonstructural protein 2, N-terminal domain, coronavirus / Non-structural protein 2, C-terminal domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Peptidase family C16 domain profile. / : / : / Coronavirus replicase NSP7 / Coronavirus 3Ecto domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Coronavirus main protease (M-pro) domain profile.
Similarity search - Domain/homology
Chem-QZG / Orf1a protein / ORF1ab polyprotein
Similarity search - Component
Biological speciesMiddle East respiratory syndrome-related coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.25 Å
AuthorsLovell, S. / Battaile, K.P. / Kashipathy, M.M. / Rathnayake, A.D. / Zheng, J. / Kim, Y. / Nguyen, H.N. / Chang, K.O. / Groutas, W.C.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)P30GM110761 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI109039 United States
CitationJournal: Sci Transl Med / Year: 2020
Title: 3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice.
Authors: Rathnayake, A.D. / Zheng, J. / Kim, Y. / Perera, K.D. / Mackin, S. / Meyerholz, D.K. / Kashipathy, M.M. / Battaile, K.P. / Lovell, S. / Perlman, S. / Groutas, W.C. / Chang, K.O.
History
DepositionJan 9, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 12, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 19, 2020Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Sep 2, 2020Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Orf1a protein
B: Orf1a protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,5084
Polymers68,6282
Non-polymers8792
Water3,081171
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2080 Å2
ΔGint-15 kcal/mol
Surface area24190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.201, 91.726, 101.586
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Orf1a protein


Mass: 34314.242 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Middle East respiratory syndrome-related coronavirus
Gene: orf1a / Plasmid: pET28 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: A0A1L2E0X0, UniProt: T2B9U0*PLUS
#2: Chemical ChemComp-QZG / N-{(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-N~2~-({[trans-4-(propan-2-yl)cyclohexyl]oxy}carbonyl)-L-leucinamide


Mass: 439.589 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H41N3O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 171 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.59 Å3/Da / Density % sol: 52.45 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5 / Details: 8% (w/v) PEG 8000, 100 mM sodium citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 3, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.25→44.44 Å / Num. obs: 34478 / % possible obs: 99.9 % / Redundancy: 6.6 % / CC1/2: 0.996 / Rmerge(I) obs: 0.127 / Net I/σ(I): 9.8 / Num. measured all: 228970 / Scaling rejects: 6
Reflection shellResolution: 2.25→2.32 Å / Redundancy: 6.5 % / Rmerge(I) obs: 1.097 / Num. measured all: 20365 / Num. unique obs: 3115 / CC1/2: 0.725 / Net I/σ(I) obs: 1.9 / % possible all: 99.8

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation6.56 Å44.44 Å
Translation6.56 Å44.44 Å

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.7.4data scaling
PHASER2.8.3phasing
PHENIXdev_3587refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WKK

5wkk


Resolution: 2.25→42.264 Å / SU ML: 0.29 / Cross valid method: THROUGHOUT / σ(F): 1.05 / Phase error: 25.61 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2479 1634 4.75 %
Rwork0.1865 32780 -
obs0.1894 34414 99.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 100.47 Å2 / Biso mean: 42.6656 Å2 / Biso min: 20.13 Å2
Refinement stepCycle: final / Resolution: 2.25→42.264 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4430 0 59 171 4660
Biso mean--40.44 42.99 -
Num. residues----594
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
2.2501-2.31630.32891460.25432669
2.3163-2.39110.321110.23672700
2.3911-2.47650.26761500.21962698
2.4765-2.57570.27881490.21272660
2.5757-2.69290.27441270.20342730
2.6929-2.83480.26281240.20152701
2.8348-3.01240.2581380.19842725
3.0124-3.24490.27011540.21112701
3.2449-3.57130.24511260.18972741
3.5713-4.08770.24521350.17292756
4.0877-5.14870.20591390.142781
5.1487-42.2640.22451350.18342918

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