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- PDB-6ts5: Coagulation factor XI protease domain in complex with active site... -

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Basic information

Entry
Database: PDB / ID: 6ts5
TitleCoagulation factor XI protease domain in complex with active site inhibitor
ComponentsCoagulation factor XI
KeywordsHYDROLASE / S1 protease / serine protease / structure-based drug design / active site directed inhibitor
Function / homology
Function and homology information


coagulation factor XIa / serine-type aminopeptidase activity / Defective F9 activation / positive regulation of fibrinolysis / plasminogen activation / Intrinsic Pathway of Fibrin Clot Formation / blood coagulation / heparin binding / serine-type endopeptidase activity / extracellular space ...coagulation factor XIa / serine-type aminopeptidase activity / Defective F9 activation / positive regulation of fibrinolysis / plasminogen activation / Intrinsic Pathway of Fibrin Clot Formation / blood coagulation / heparin binding / serine-type endopeptidase activity / extracellular space / extracellular exosome / extracellular region / identical protein binding / membrane / plasma membrane
Similarity search - Function
Apple domain. / Apple domain / APPLE domain / PAN/Apple domain profile. / PAN domain / PAN/Apple domain / 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. ...Apple domain. / Apple domain / APPLE domain / PAN/Apple domain profile. / PAN domain / PAN/Apple domain / 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 / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-NW2 / Coagulation factor XI
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.29 Å
AuthorsRenatus, M. / Schiering, N.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach.
Authors: Lorthiois, E. / Roache, J. / Barnes-Seeman, D. / Altmann, E. / Hassiepen, U. / Turner, G. / Duvadie, R. / Hornak, V. / Karki, R.G. / Schiering, N. / Weihofen, W.A. / Perruccio, F. / Calhoun, ...Authors: Lorthiois, E. / Roache, J. / Barnes-Seeman, D. / Altmann, E. / Hassiepen, U. / Turner, G. / Duvadie, R. / Hornak, V. / Karki, R.G. / Schiering, N. / Weihofen, W.A. / Perruccio, F. / Calhoun, A. / Fazal, T. / Dedic, D. / Durand, C. / Dussauge, S. / Fettis, K. / Tritsch, F. / Dentel, C. / Druet, A. / Liu, D. / Kirman, L. / Lachal, J. / Namoto, K. / Bevan, D. / Mo, R. / Monnet, G. / Muller, L. / Zessis, R. / Huang, X. / Lindsley, L. / Currie, T. / Chiu, Y.H. / Fridrich, C. / Delgado, P. / Wang, S. / Hollis-Symynkywicz, M. / Berghausen, J. / Williams, E. / Liu, H. / Liang, G. / Kim, H. / Hoffmann, P. / Hein, A. / Ramage, P. / D'Arcy, A. / Harlfinger, S. / Renatus, M. / Ruedisser, S. / Feldman, D. / Elliott, J. / Sedrani, R. / Maibaum, J. / Adams, C.M.
History
DepositionDec 20, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 8, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2May 1, 2024Group: 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

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Assembly

Deposited unit
A: Coagulation factor XI
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,7487
Polymers26,8561
Non-polymers8926
Water4,828268
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area730 Å2
ΔGint-24 kcal/mol
Surface area11740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.990, 60.600, 66.920
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Coagulation factor XI / FXI / Plasma thromboplastin antecedent / PTA


Mass: 26856.496 Da / Num. of mol.: 1
Mutation: SER A 123 SWS P03951 CYS 500 ENGINEERED MUTATION, ALA A 195 SWS P03951 SER 575 ACTIVE SITE MUTATION
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F11 / Production host: Escherichia coli (E. coli) / References: UniProt: P03951, coagulation factor XIa
#2: Chemical ChemComp-NW2 / 2-[2-[3-[(3~{S})-3-azanyl-2,3-dihydro-1-benzofuran-5-yl]-5-propan-2-yl-phenyl]ethoxy]-3-methoxy-benzoic acid


Mass: 447.523 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H29NO5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 268 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.27 Å3/Da / Density % sol: 45.84 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.2 M Ammonium sulfate, 0.1 M BIS-TRIS pH5.5, 25% w/v Polyethylene glycol 3350 Protein at 18mg/ml in 50mM Tris/HCl pH7.4 100mM NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99987 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Mar 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99987 Å / Relative weight: 1
ReflectionResolution: 1.29→66.91 Å / Num. obs: 61671 / % possible obs: 99.5 % / Redundancy: 4.844 % / Biso Wilson estimate: 20.038 Å2 / Rmerge(I) obs: 0.042 / Rrim(I) all: 0.047 / Χ2: 1.062 / Net I/σ(I): 17.08
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRrim(I) all% possible all
1.29-1.324.9120.423.4344630.47199.9
1.32-1.364.8390.3553.9444340.39999.8
1.36-1.44.6480.2814.7442540.31798.7
1.4-1.444.8790.2276.0241450.25599.7
1.44-1.495.0610.1837.640470.20599.8
1.49-1.545.070.1529.1439100.1799.7
1.54-1.65.0080.12610.9737830.14199.7
1.6-1.674.9240.10313.2836600.11599.6
1.67-1.744.5210.08714.9334490.09898.9
1.74-1.825.1060.07119.5333540.0899.6
1.82-1.924.9960.05823.2831950.06599.8
1.92-2.044.9030.0526.5730440.05699.6
2.04-2.184.7770.04529.5128270.05199.1
2.18-2.364.4070.04229.7826240.04798.6
2.36-2.584.5470.0383224590.04399.1
2.58-2.884.9260.03635.9822350.0499.5
2.88-3.334.8260.03238.2719890.03699.6
3.33-4.084.6270.0339.2616840.03499.1
4.08-5.774.5430.02639.3713220.02998.4
5.77-66.914.8680.02440.287930.02799.9

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XSCALEJuly 4, 2012data scaling
PDB_EXTRACT3.25data extraction
BUSTER2.11.7phasing
XDSdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: inhouse structure

Resolution: 1.29→44.92 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.94 / SU R Cruickshank DPI: 0.05 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.053 / SU Rfree Blow DPI: 0.054 / SU Rfree Cruickshank DPI: 0.051
RfactorNum. reflection% reflectionSelection details
Rfree0.2075 3020 -RANDOM
Rwork0.1875 ---
obs0.1885 61671 99.5 %-
Displacement parametersBiso mean: 18.48 Å2
Baniso -1Baniso -2Baniso -3
1-2.6746 Å20 Å20 Å2
2---3.8028 Å20 Å2
3---1.1283 Å2
Refine analyzeLuzzati coordinate error obs: 0.17 Å
Refinement stepCycle: LAST / Resolution: 1.29→44.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1875 0 56 268 2199
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082045HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.032791HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d716SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes350HARMONIC5
X-RAY DIFFRACTIONt_it2045HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion260SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2025SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion4.59
X-RAY DIFFRACTIONt_other_torsion14.08
LS refinement shellResolution: 1.29→1.3 Å
RfactorNum. reflection% reflection
Rfree0.2471 62 -
Rwork0.2013 --
obs0.2035 1234 100 %

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