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

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Basic information

Entry
Database: PDB / ID: 7meq
TitleCrystal structure of human TMPRSS2 in complex with Nafamostat
ComponentsTransmembrane protease serine 2
KeywordsHYDROLASE/HYDROLASE INHIBITOR / COVID19 / protease / HYDROLASE-HYDROLASE INHIBITOR complex
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 / Attachment and Entry / positive regulation of viral entry into host cell / serine-type endopeptidase activity / proteolysis ...transmembrane protease serine 2 / protein autoprocessing / Attachment and Entry / serine-type peptidase activity / viral translation / Induction of Cell-Cell Fusion / 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 / SRCR domain profile. / SRCR-like domain / SRCR-like domain superfamily / Scavenger receptor Cys-rich / 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 ...Scavenger receptor cysteine-rich domain / SRCR domain / SRCR domain profile. / SRCR-like domain / SRCR-like domain superfamily / Scavenger receptor Cys-rich / 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 / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / 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 / molecular replacement / Resolution: 1.95 Å
AuthorsFraser, B. / Beldar, S. / Hutchinson, A. / Li, Y. / Seitova, A. / Edwards, A.M. / Benard, F. / Arrowsmith, C.H. / Halabelian, L. / Structural Genomics Consortium (SGC)
Citation
Journal: Nat.Chem.Biol. / Year: 2022
Title: Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation.
Authors: Fraser, B.J. / Beldar, S. / Seitova, A. / Hutchinson, A. / Mannar, D. / Li, Y. / Kwon, D. / Tan, R. / Wilson, R.P. / Leopold, K. / Subramaniam, S. / Halabelian, L. / Arrowsmith, C.H. / Benard, F.
#1: Journal: Biorxiv / Year: 2021
Title: Structure, activity and inhibition of human TMPRSS2, a protease implicated in SARS-CoV-2 activation
Authors: Fraser, B.J. / Beldar, S. / Seitova, A. / Hutchinson, A. / Mannar, D. / Li, Y. / Kwon, D. / Tan, R. / Wilson, R.P. / Leopold, K. / Subramaniam, S. / Halabelian, L. / Arrowsmith, C.H. / Benard, F.
History
DepositionApr 7, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 21, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 3, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Jun 22, 2022Group: Database references / Category: citation / citation_author
Revision 1.3Sep 7, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.4Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / pdbx_initial_refinement_model
Item: _citation.journal_id_ISSN

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transmembrane protease serine 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,4976
Polymers43,8931
Non-polymers6045
Water2,126118
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)59.445, 51.425, 64.353
Angle α, β, γ (deg.)90.000, 91.530, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Transmembrane protease serine 2 / Serine protease 10


Mass: 43893.316 Da / Num. of mol.: 1
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, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#2: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#3: Chemical ChemComp-GBS / 4-carbamimidamidobenzoic acid / Nafamostat, bound form


Mass: 179.176 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H9N3O2 / Feature type: SUBJECT OF INVESTIGATION
Comment: anticancer, anticoagulant, antivirus, protease inhibitor*YM
#4: Chemical ChemComp-UNX / UNKNOWN ATOM OR ION


Num. of mol.: 3 / Source method: obtained synthetically
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 118 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Sequence detailsIn this construct Ser250 is deleted and residues 251-255 are replaced with 251-DDDDK-255 to modify ...In this construct Ser250 is deleted and residues 251-255 are replaced with 251-DDDDK-255 to modify autoproteolytic activity. The protein is expressed as a zymogen and activated through autoproteolytic cleavage of loop region residues 255-256. The cleaved I256 adopts a catalytically active mode by forming a salt bridge with Asp440. A similar activation mechanism has been observed for other proteases such as PDB ID 6KD5.

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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: 2.24 Å3/Da / Density % sol: 45.09 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 30.0% (w/v) Jeffamine ED-2001 7.0, 0.1 M HEPES pH7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 13, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.95→43.08 Å / Num. obs: 27823 / % possible obs: 97.6 % / Redundancy: 4.4 % / Biso Wilson estimate: 33.02 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.038 / Rrim(I) all: 0.085 / Net I/σ(I): 8.9 / Num. measured all: 121763 / Scaling rejects: 1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.95-24.30.811850819710.7790.4240.9221.598.9
8.94-43.084.50.03413543020.9980.0160.03834.192.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
BUSTER2.10.3refinement
XDSdata reduction
Aimless0.7.4data scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1z8g

1z8g


Resolution: 1.95→40.17 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.925 / SU R Cruickshank DPI: 0.147 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.147 / SU Rfree Blow DPI: 0.135 / SU Rfree Cruickshank DPI: 0.136
RfactorNum. reflection% reflectionSelection details
Rfree0.225 1322 4.76 %RANDOM
Rwork0.192 ---
obs0.193 27797 97.3 %-
Displacement parametersBiso max: 143.93 Å2 / Biso mean: 54.14 Å2 / Biso min: 25.29 Å2
Baniso -1Baniso -2Baniso -3
1--19.4208 Å20 Å2-7.66 Å2
2--5.0472 Å20 Å2
3---14.3736 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: final / Resolution: 1.95→40.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2482 0 43 118 2643
Biso mean--80.77 45.95 -
Num. residues----326
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d825SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes442HARMONIC5
X-RAY DIFFRACTIONt_it2598HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion338SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2909SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2598HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3550HARMONIC21.04
X-RAY DIFFRACTIONt_omega_torsion3.29
X-RAY DIFFRACTIONt_other_torsion17.06
LS refinement shellResolution: 1.95→1.96 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2431 23 4.14 %
Rwork0.2226 533 -
all0.2232 556 -
obs--97.3 %
Refinement TLS params.Method: refined / Origin x: 7.3127 Å / Origin y: -8.3286 Å / Origin z: 13.8778 Å
111213212223313233
T0.1856 Å20.0184 Å20.0754 Å2--0.2074 Å2-0.0142 Å2---0.1874 Å2
L0.8045 °20.0343 °2-0.165 °2-1.1951 °2-0.1946 °2--2.1824 °2
S-0.012 Å °0.0613 Å °-0.0408 Å °-0.0716 Å °0.031 Å °-0.0976 Å °0.0925 Å °0.1445 Å °-0.019 Å °
Refinement TLS groupSelection details: { A|* }

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