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- PDB-8hd8: Crystal structure of TMPRSS2 in complex with 212-148 -

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Basic information

Entry
Database: PDB / ID: 8hd8
TitleCrystal structure of TMPRSS2 in complex with 212-148
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 / symbiont-mediated induction of syncytium formation / 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 ...transmembrane protease serine 2 / symbiont-mediated induction of syncytium formation / 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 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: 2.4 Å
AuthorsWang, H. / 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
DepositionNov 3, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 13, 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)88,4839
Polymers87,8234
Non-polymers6605
Water4,756264
1
A: Transmembrane protease serine 2 catalytic chain
C: Transmembrane protease serine 2 catalytic chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,1314
Polymers43,9112
Non-polymers2192
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2610 Å2
ΔGint-10 kcal/mol
Surface area16330 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 area3020 Å2
ΔGint-9 kcal/mol
Surface area16520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.474, 93.835, 94.243
Angle α, β, γ (deg.)90.00, 101.13, 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 were 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, 1 molecules

#5: 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.: 1 / 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, 268 molecules

#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#4: 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
Comment: anticancer, anticoagulant, antivirus, protease inhibitor*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 264 / 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: 2.45 Å3/Da / Density % sol: 49.69 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
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: BL10U2 / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 4, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.4→46.92 Å / Num. obs: 33102 / % possible obs: 99.6 % / Redundancy: 4.41 % / CC1/2: 0.995 / Rmerge(I) obs: 0.12 / Rrim(I) all: 0.135 / Net I/σ(I): 9.98
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2.4-2.540.70853160.6120.8291
2.54-2.720.48750240.7980.561
2.72-2.940.35246670.9160.3961
2.94-3.220.21842830.9720.2441
3.22-3.60.12439170.9890.1391
3.6-4.150.07834380.9950.0881
4.15-5.080.05829100.9970.0651
5.08-7.180.06322840.9960.0711
7.18-46.920.0412630.9970.0461

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Processing

Software
NameVersionClassification
XDS2020-12-02data scaling
PHENIX1.20.1-4487-000refinement
PDB_EXTRACT3.27data extraction
XDS2020-12-02data reduction
PHENIX1.20.1-4487-000phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7MEQ

7meq


Resolution: 2.4→46.92 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 21.87 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2176 1993 6.02 %
Rwork0.1818 --
obs0.184 33097 99.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.4→46.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5681 0 40 264 5985
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0055888
X-RAY DIFFRACTIONf_angle_d1.0778022
X-RAY DIFFRACTIONf_dihedral_angle_d7.774807
X-RAY DIFFRACTIONf_chiral_restr0.055857
X-RAY DIFFRACTIONf_plane_restr0.0061038
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.460.31631400.28282220X-RAY DIFFRACTION99
2.46-2.530.30831330.2642207X-RAY DIFFRACTION100
2.53-2.60.29151550.23492203X-RAY DIFFRACTION99
2.6-2.680.29511430.22552170X-RAY DIFFRACTION100
2.68-2.780.25081360.21912249X-RAY DIFFRACTION100
2.78-2.890.2521450.22052207X-RAY DIFFRACTION100
2.89-3.020.25881380.22362231X-RAY DIFFRACTION100
3.02-3.180.25661470.19422195X-RAY DIFFRACTION100
3.18-3.380.2441390.18632241X-RAY DIFFRACTION100
3.38-3.640.19871440.1772208X-RAY DIFFRACTION100
3.64-4.010.20571420.15532235X-RAY DIFFRACTION100
4.01-4.590.15791400.13792235X-RAY DIFFRACTION100
4.59-5.780.18471440.14782240X-RAY DIFFRACTION100
5.78-46.920.1771470.16682263X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.9067-0.4349-0.32482.2874-0.3910.39650.0909-0.3762-0.11480.3625-0.1663-0.69330.02710.33280.13730.3634-0.0303-0.07770.43350.03240.552319.04810.28719.828
21.28910.160.31561.1053-0.38711.4489-0.11710.21840.12540.0713-0.0536-0.5019-0.30260.3520.20370.3616-0.0564-0.03990.35460.07040.426914.42518.2879.085
30.4229-0.50760.08020.963-0.66550.9367-0.16450.12070.21540.3482-0.2794-0.2875-0.1190.65130.23050.3995-0.0804-0.11030.41380.10640.426312.82420.7329.892
41.4531-0.08420.27541.28280.1831.20260.0143-0.0558-0.0510.0046-0.03960.00580.1322-0.02950.03650.2520.0002-0.0050.240.00160.2474-1.839-7.80611.456
51.4678-0.13590.38891.4053-0.17781.56470.0051-0.1754-0.1120.152-0.1029-0.06330.0347-0.12290.0770.2459-0.0313-0.00720.25570.0010.2217-1.88-2.56621.62
61.76950.89660.74920.52140.2670.6081-0.18170.1080.5818-0.1685-0.23950.1567-0.3686-0.49440.31970.4866-0.01380.00430.5756-0.11490.3802-23.3021.77-49.174
71.1644-0.82260.58770.95050.0680.91860.14220.2659-0.4811-0.1612-0.1960.08370.9039-0.14930.12880.7051-0.01380.05090.5212-0.0920.4851-16.917-14.227-38.102
80.8229-0.0073-0.21970.2104-0.19730.2399-0.03440.2088-0.24660.1034-0.018-0.00580.4764-0.33010.05170.64320.02280.04540.469-0.10030.4555-18.601-13.103-29.563
91.3160.084-0.04551.30350.01391.6747-0.02050.07770.09550.07360.02970.0709-0.0386-0.07070.01260.21770.00610.01110.22270.00840.2541-17.0329.447-19.082
101.1328-0.06410.13762.0347-0.02871.6576-0.0380.2253-0.0719-0.18690.00890.1040.0053-0.04610.01540.2796-0.03310.02430.2702-0.01790.2831-21.7855.255-24.868
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 117:162 )A117 - 162
2X-RAY DIFFRACTION2( CHAIN A AND RESID 163:220 )A163 - 220
3X-RAY DIFFRACTION3( CHAIN A AND RESID 221:245 )A221 - 245
4X-RAY DIFFRACTION4( CHAIN A AND RESID 246:250 ) OR ( CHAIN C AND RESID 256:410 )A246 - 250
5X-RAY DIFFRACTION4( CHAIN A AND RESID 246:250 ) OR ( CHAIN C AND RESID 256:410 )C256 - 410
6X-RAY DIFFRACTION5( CHAIN C AND RESID 411:495 )C411 - 495
7X-RAY DIFFRACTION6( CHAIN B AND RESID 113:146 )B113 - 146
8X-RAY DIFFRACTION7( CHAIN B AND RESID 147:220 )B147 - 220
9X-RAY DIFFRACTION8( CHAIN B AND RESID 221:253 ) OR ( CHAIN D AND RESID 256:257 )B221 - 253
10X-RAY DIFFRACTION8( CHAIN B AND RESID 221:253 ) OR ( CHAIN D AND RESID 256:257 )D256 - 257
11X-RAY DIFFRACTION9( CHAIN D AND RESID 258:443 )D258 - 443
12X-RAY DIFFRACTION10( CHAIN D AND RESID 444:494 )D444 - 494

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