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- PDB-5wkl: 1.85 A resolution structure of MERS 3CL protease in complex with ... -

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Basic information

Entry
Database: PDB / ID: 5wkl
Title1.85 A resolution structure of MERS 3CL protease in complex with piperidine-based peptidomimetic inhibitor 17
ComponentsOrf1a proteinORF1ab
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PROTEASE / protease Inhhibitors / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


host cell membrane / viral genome replication / methyltransferase activity / methylation / SARS coronavirus main proteinase / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / omega peptidase activity ...host cell membrane / viral genome replication / methyltransferase activity / methylation / SARS coronavirus main proteinase / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / omega peptidase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / symbiont-mediated perturbation of host ubiquitin-like protein modification / endonuclease activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / host cell perinuclear region of cytoplasm / viral protein processing / induction by virus of host autophagy / symbiont-mediated suppression of host gene expression / cysteine-type endopeptidase activity / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / proteolysis / zinc ion binding / membrane
Similarity search - Function
Non-structural protein 2, MERS-CoV-like / NSP3, SUD-C domain, MERS-CoV-like / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / Coronavirus 3Ecto domain profile. / : / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / NSP1, C-terminal domain, betacoronavirus / Betacoronavirus Nsp3c-M domain profile. / NSP1, globular domain, betacoronavirus ...Non-structural protein 2, MERS-CoV-like / NSP3, SUD-C domain, MERS-CoV-like / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / Coronavirus 3Ecto domain profile. / : / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / NSP1, C-terminal domain, betacoronavirus / 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 / Betacoronavirus (BetaCoV) Nsp1 C-terminal 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 superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Papain-like protease, N-terminal domain superfamily, coronavirus / Papain-like viral protease, palm and finger domains, coronavirus / : / Coronavirus (CoV) Nsp2 middle domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / NSP1, globular domain, alpha/betacoronavirus / : / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl 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. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Papain-like protease, thumb domain superfamily, coronavirus / Coronavirus replicase NSP7 / Peptidase family C16 domain profile. / Non-structural protein NSP7, coronavirus / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, coronavirus / Non-structural protein NSP8, coronavirus / RNA synthesis protein NSP10, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / RNA synthesis protein NSP10 superfamily, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Non-structural protein NSP7 superfamily, coronavirus / Non-structural protein NSP8 superfamily, coronavirus / Non-structural protein NSP4, C-terminal superfamily, coronavirus / Peptidase C30, domain 3, coronavirus / Non-structural protein 6, coronavirus / Coronavirus replicase NSP3, C-terminal / Non-structural protein NSP4, N-terminal, coronavirus / Coronavirus endopeptidase C30 / Coronavirus papain-like peptidase / Coronavirus replicase NSP8 / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP6 / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Coronavirus main protease (M-pro) domain profile. / Coronavirus replicase NSP9 / Non-structural protein 3, X-domain-like / Trypsin-like serine proteases / Macro domain / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain-like / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-AVY / Chem-B3J / Orf1a protein / Replicase polyprotein 1a
Similarity search - Component
Biological speciesMiddle East respiratory syndrome-related coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.85 Å
AuthorsLovell, S. / Battaile, K.P. / Mehzabeen, N. / Kankanamalage, A.C.G. / Kim, Y. / Rathnayake, A.D. / Chang, K.O. / Groutas, W.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)P30GM110761 United States
CitationJournal: Eur J Med Chem / Year: 2018
Title: Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element.
Authors: Galasiti Kankanamalage, A.C. / Kim, Y. / Damalanka, V.C. / Rathnayake, A.D. / Fehr, A.R. / Mehzabeen, N. / Battaile, K.P. / Lovell, S. / Lushington, G.H. / Perlman, S. / Chang, K.O. / Groutas, W.C.
History
DepositionJul 25, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 4, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 4, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Orf1a protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6523
Polymers34,3141
Non-polymers1,3382
Water2,306128
1
A: Orf1a protein
hetero molecules

A: Orf1a protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,3046
Polymers68,6282
Non-polymers2,6754
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area2460 Å2
ΔGint-16 kcal/mol
Surface area23960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.253, 58.099, 49.734
Angle α, β, γ (deg.)90.000, 112.000, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-622-

HOH

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Components

#1: Protein Orf1a protein / ORF1ab


Mass: 34314.242 Da / Num. of mol.: 1 / Fragment: Peptidase C30 domain residues 3248-3553
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 (E. coli) / Strain (production host): BL21 / References: UniProt: A0A1L2E0X0, UniProt: K9N638*PLUS
#2: Chemical ChemComp-AVY / (1R,2S)-2-{[N-({[4-benzyl-1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}carbonyl)-L-leucyl]amino}-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid / bound form / Bound and free morphemes


Mass: 668.799 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H48N4O10S
#3: Chemical ChemComp-B3J / (1S,2S)-2-{[N-({[4-benzyl-1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}carbonyl)-L-leucyl]amino}-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 668.799 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H48N4O10S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 128 / 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: 1.98 Å3/Da / Density % sol: 37.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 25% (w/v) PEG 3350, 100 mM Bis-Tris, 200 mM MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 25, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→46.94 Å / Num. obs: 22772 / % possible obs: 99.1 % / Redundancy: 3.3 % / Biso Wilson estimate: 22.32 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.078 / Net I/σ(I): 11.3
Reflection shell

Diffraction-ID: 1 / Redundancy: 3.2 %

Resolution (Å)Rmerge(I) obsNum. measured obsNum. unique allCC1/2% possible all
1.85-1.890.686450214000.77499
9.06-46.940.0250.99992.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.5.25data scaling
PHASERphasing
PHENIX(dev_2838)refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4RSP

4rsp


Resolution: 1.85→46.938 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.01 / Phase error: 22.5
RfactorNum. reflection% reflection
Rfree0.2119 1127 4.95 %
Rwork0.163 --
obs0.1655 22761 99.02 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 80.38 Å2 / Biso mean: 28.4508 Å2 / Biso min: 10.84 Å2
Refinement stepCycle: final / Resolution: 1.85→46.938 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2242 0 60 128 2430
Biso mean--27.39 32.9 -
Num. residues----303
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012376
X-RAY DIFFRACTIONf_angle_d1.0723247
X-RAY DIFFRACTIONf_chiral_restr0.058378
X-RAY DIFFRACTIONf_plane_restr0.007409
X-RAY DIFFRACTIONf_dihedral_angle_d11.6891358
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.85-1.93420.27231210.23832698281999
1.9342-2.03620.25531480.19662691283999
2.0362-2.16380.24211520.17227172869100
2.1638-2.33090.22251320.16612703283599
2.3309-2.56540.23411380.16482697283599
2.5654-2.93660.22461420.16582710285299
2.9366-3.69950.21391490.1562686283599
3.6995-46.95350.16991450.1452732287798

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