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- PDB-7xyd: Crystal structure of TMPRSS2 in complex with Nafamostat -

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Basic information

Entry
Database: PDB / ID: 7xyd
TitleCrystal structure of TMPRSS2 in complex with Nafamostat
Components(Transmembrane protease serine 2 catalytic ...) x 2
KeywordsHYDROLASE / Inhibitor / Complex / Host / Antiviral / ANTIVIRAL PROTEIN
Function / homology
Function and homology information


transmembrane protease serine 2 / protein autoprocessing / Attachment and Entry / serine-type peptidase activity / viral translation / Induction of Cell-Cell Fusion / entry receptor-mediated virion attachment to host cell / Attachment and Entry / positive regulation of viral entry into host cell / serine-type endopeptidase activity ...transmembrane protease serine 2 / protein autoprocessing / Attachment and Entry / serine-type peptidase activity / viral translation / Induction of Cell-Cell Fusion / entry receptor-mediated virion attachment to host cell / Attachment and Entry / positive regulation of viral entry into host cell / serine-type endopeptidase activity / proteolysis / extracellular exosome / extracellular region / nucleoplasm / plasma membrane
Similarity search - Function
Scavenger receptor cysteine-rich domain / SRCR domain profile. / SRCR-like domain superfamily / Scavenger receptor Cys-rich / SRCR domain / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat ...Scavenger receptor cysteine-rich domain / SRCR domain profile. / SRCR-like domain superfamily / Scavenger receptor Cys-rich / SRCR domain / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
4-carbamimidamidobenzoic acid / Transmembrane protease serine 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.58 Å
AuthorsWang, H. / Liu, X. / Duan, Y. / Liu, X. / Sun, L. / Yang, H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)92169109 China
CitationJournal: Nat Commun / Year: 2023
Title: Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry.
Authors: Wang, H. / Yang, Q. / Liu, X. / Xu, Z. / Shao, M. / Li, D. / Duan, Y. / Tang, J. / Yu, X. / Zhang, Y. / Hao, A. / Wang, Y. / Chen, J. / Zhu, C. / Guddat, L. / Chen, H. / Zhang, L. / Chen, X. ...Authors: Wang, H. / Yang, Q. / Liu, X. / Xu, Z. / Shao, M. / Li, D. / Duan, Y. / Tang, J. / Yu, X. / Zhang, Y. / Hao, A. / Wang, Y. / Chen, J. / Zhu, C. / Guddat, L. / Chen, H. / Zhang, L. / Chen, X. / Jiang, B. / Sun, L. / Rao, Z. / Yang, H.
History
DepositionJun 1, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 6, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 13, 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: Transmembrane protease serine 2 catalytic chain
C: Transmembrane protease serine 2 catalytic chain
B: Transmembrane protease serine 2 catalytic chain
D: Transmembrane protease serine 2 catalytic chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,70410
Polymers87,8234
Non-polymers8816
Water2,756153
1
A: Transmembrane protease serine 2 catalytic chain
C: Transmembrane protease serine 2 catalytic chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,3525
Polymers43,9112
Non-polymers4403
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2840 Å2
ΔGint-8 kcal/mol
Surface area16090 Å2
MethodPISA
2
B: Transmembrane protease serine 2 catalytic chain
D: Transmembrane protease serine 2 catalytic chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,3525
Polymers43,9112
Non-polymers4403
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2720 Å2
ΔGint-7 kcal/mol
Surface area15960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.140, 93.203, 93.130
Angle α, β, γ (deg.)90.00, 100.60, 90.00
Int Tables number4
Space group name H-MP1211
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Transmembrane protease serine 2 catalytic ... , 2 types, 4 molecules ABCD

#1: Protein Transmembrane protease serine 2 catalytic chain


Mass: 16054.661 Da / Num. of mol.: 2 / Mutation: Residues 250-255 SSRQSR were mutated to DDDDK
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMPRSS2, PRSS10 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O15393
#2: Protein Transmembrane protease serine 2 catalytic chain


Mass: 27856.742 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMPRSS2, PRSS10 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O15393

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Sugars , 1 types, 2 molecules

#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 3 types, 157 molecules

#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GBS / 4-carbamimidamidobenzoic acid / Nafamostat, bound form


Mass: 179.176 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H9N3O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 153 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY
Sequence detailsChains A and C, as well as B and D, were manipulated as one single peptide, but auto-cleaved at ...Chains A and C, as well as B and D, were manipulated as one single peptide, but auto-cleaved at residue 256 during zymogen activation.

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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: 2.36 Å3/Da / Density % sol: 47.9 % / Description: Plate
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4
Details: 0.1M acetic acid/sodium acetate, pH 4.0, 20% w/v PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.9793 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 16, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.58→39.81 Å / Num. obs: 25667 / % possible obs: 98.5 % / Redundancy: 5.29 % / CC1/2: 0.989 / Rmerge(I) obs: 0.171 / Rrim(I) all: 0.19 / Net I/σ(I): 8.11
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2.58-2.740.84541230.6450.9361
2.74-2.930.59639210.7970.661
2.93-3.160.37635730.9050.4191
3.16-3.460.23633830.9640.2611
3.46-3.860.1430440.9830.1561
3.86-4.460.09426320.9930.1041
4.46-5.450.07922900.9940.0881
5.45-7.660.08817010.9940.0981
7.66-39.810.06210000.9950.0691

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
XDS2020-12-02data reduction
XDS2020-12-02data scaling
PHENIX1.18.2_3874phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Model predicted by AlphaFold

Resolution: 2.58→39.81 Å / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 25.64 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2477 2004 7.81 %
Rwork0.2114 --
obs0.2142 25657 98.52 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.58→39.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5623 0 54 153 5830
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0065829
X-RAY DIFFRACTIONf_angle_d0.8227939
X-RAY DIFFRACTIONf_dihedral_angle_d16.4992019
X-RAY DIFFRACTIONf_chiral_restr0.056844
X-RAY DIFFRACTIONf_plane_restr0.011027
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.58-2.650.40361520.31431628X-RAY DIFFRACTION98
2.65-2.720.31951320.26931727X-RAY DIFFRACTION99
2.72-2.80.3271410.27651687X-RAY DIFFRACTION99
2.8-2.890.31841500.26261707X-RAY DIFFRACTION100
2.89-2.990.32461460.26481683X-RAY DIFFRACTION100
2.99-3.110.26711310.25171685X-RAY DIFFRACTION97
3.11-3.250.32671530.22571684X-RAY DIFFRACTION99
3.25-3.420.26161460.22121696X-RAY DIFFRACTION100
3.42-3.640.25211470.20891715X-RAY DIFFRACTION100
3.64-3.920.2191430.19151682X-RAY DIFFRACTION99
3.92-4.310.22061410.17331651X-RAY DIFFRACTION97
4.31-4.930.1851420.16631736X-RAY DIFFRACTION99
4.94-6.210.20011330.19441669X-RAY DIFFRACTION96
6.22-39.810.19511470.19231703X-RAY DIFFRACTION97

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