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- PDB-7y0f: Crystal structure of TMPRSS2 in complex with UK-371804 -

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Basic information

Entry
Database: PDB / ID: 7y0f
TitleCrystal structure of TMPRSS2 in complex with UK-371804
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
Chem-I9V / Transmembrane protease serine 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsWang, H. / 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 4, 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)89,11710
Polymers87,8234
Non-polymers1,2946
Water1,65792
1
A: Transmembrane protease serine 2 catalytic chain
C: Transmembrane protease serine 2 catalytic chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,5595
Polymers43,9112
Non-polymers6473
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2870 Å2
ΔGint-7 kcal/mol
Surface area15850 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)44,5595
Polymers43,9112
Non-polymers6473
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2830 Å2
ΔGint-11 kcal/mol
Surface area15100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.045, 91.208, 90.696
Angle α, β, γ (deg.)90.00, 100.44, 90.00
Int Tables number4
Space group name H-MP1211

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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) in the database have been replaced with 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
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, 96 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-I9V / 2-[(1-carbamimidamido-4-chloranyl-isoquinolin-7-yl)sulfonylamino]-2-methyl-propanoic acid / UK-371804


Mass: 385.826 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H16ClN5O4S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 92 / 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: 2.23 Å3/Da / Density % sol: 44.75 % / Description: Plate
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1M acetic acid/sodium acetate, pH 5.0, 16% w/v PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.979175 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Jan 27, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979175 Å / Relative weight: 1
ReflectionResolution: 2.6→47.25 Å / Num. obs: 23484 / % possible obs: 98.7 % / Redundancy: 3.42 % / CC1/2: 0.985 / Rmerge(I) obs: 0.161 / Rrim(I) all: 0.191 / Net I/σ(I): 8.48
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2.6-2.760.88237150.6381.0441
2.76-2.950.62335250.7760.7361
2.95-3.180.35932930.9030.4251
3.18-3.480.22630650.9480.2681
3.48-3.890.13227580.9810.1561
3.89-4.490.0824670.9920.0961
4.49-5.490.07120880.9930.0851
5.49-7.710.07216310.9920.0861
7.71-47.250.0389420.9970.0461

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
XDS2020-12-02data scaling
PDB_EXTRACT3.27data extraction
XDS2020-12-02data reduction
PHENIX1.18.2_3874phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Model predicted by Alphafold

Resolution: 2.6→47.25 Å / SU ML: 0.37 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 24.14 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2374 2010 8.56 %
Rwork0.217 --
obs0.2188 23468 98.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.6→47.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5552 0 80 92 5724
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0135780
X-RAY DIFFRACTIONf_angle_d1.4017890
X-RAY DIFFRACTIONf_dihedral_angle_d14.4762003
X-RAY DIFFRACTIONf_chiral_restr0.097846
X-RAY DIFFRACTIONf_plane_restr0.0091010
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.670.35881330.34711487X-RAY DIFFRACTION95
2.67-2.740.33741510.31381505X-RAY DIFFRACTION99
2.74-2.820.2971470.29611531X-RAY DIFFRACTION99
2.82-2.910.31181370.27911492X-RAY DIFFRACTION98
2.91-3.010.27941390.26171551X-RAY DIFFRACTION98
3.01-3.130.27341410.24411520X-RAY DIFFRACTION99
3.13-3.280.25581520.2391509X-RAY DIFFRACTION99
3.28-3.450.2361340.22361563X-RAY DIFFRACTION99
3.45-3.660.21761450.19291542X-RAY DIFFRACTION99
3.66-3.950.21161470.19111541X-RAY DIFFRACTION99
3.95-4.340.21141470.16951535X-RAY DIFFRACTION99
4.34-4.970.19561470.17931546X-RAY DIFFRACTION100
4.97-6.260.21561450.20851559X-RAY DIFFRACTION100
6.27-47.250.2061450.19281577X-RAY DIFFRACTION98

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