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- PDB-4wxi: FACTOR XIA IN COMPLEX WITH THE INHIBITOR trans-N-{(1S)-1-[4-(3-am... -

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Basic information

Entry
Database: PDB / ID: 4wxi
TitleFACTOR XIA IN COMPLEX WITH THE INHIBITOR trans-N-{(1S)-1-[4-(3-amino-2H-indazol-6-yl)pyridin-2-yl]-2-phenylethyl}-4-(aminomethyl)cyclohexanecarboxamide
ComponentsCOAGULATION FACTOR XI, LIGHT CHAIN
Keywordshydrolase/hydrolase inhibitor / HYDROLASE / SERINE PROTEASE / BLOOD COAGULATION FACTOR / PROTEIN INHIBITOR COMPLEX / hydrolase-hydrolase inhibitor complex
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 family, serine active site. / Serine proteases, trypsin domain profile. / 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-3VM / Coagulation factor XI
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsWei, A.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Pyridine and pyridinone-based factor XIa inhibitors.
Authors: Corte, J.R. / Fang, T. / Hangeland, J.J. / Friends, T.J. / Rendina, A.R. / Luettgen, J.M. / Bozarth, J.M. / Barbera, F.A. / Rossi, K.A. / Wei, A. / Ramamurthy, V. / Morin, P.E. / Seiffert, D. ...Authors: Corte, J.R. / Fang, T. / Hangeland, J.J. / Friends, T.J. / Rendina, A.R. / Luettgen, J.M. / Bozarth, J.M. / Barbera, F.A. / Rossi, K.A. / Wei, A. / Ramamurthy, V. / Morin, P.E. / Seiffert, D.A. / Wexler, R.R. / Quan, M.L.
#1: Journal: J.Med.Chem. / Year: 2014
Title: Tetrahydroquinoline Derivatives as Potent and Selective Factor XIa Inhibitor
Authors: Quan, M.L. / Wong, P.C. / Woerner, F. / Smallheer, J.M. / Barbera, F.A. / Bozrarth, J.M. / Brown, R.L. / Harpel, M.R. / Luettgen, J.M. / Morin, P.E. / Peterson, T. / Ramamurthy, V. / ...Authors: Quan, M.L. / Wong, P.C. / Woerner, F. / Smallheer, J.M. / Barbera, F.A. / Bozrarth, J.M. / Brown, R.L. / Harpel, M.R. / Luettgen, J.M. / Morin, P.E. / Peterson, T. / Ramamurthy, V. / Rendina, A.R. / Rossi, K.A. / Watson, C.A. / Wei, A. / Zhang, G. / Sieffert, D. / Wexler, R.R.
#2: Journal: J.Med.Chem. / Year: 2014
Title: Phenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with in Vivo Antithrombotic Activity
Authors: Hangeland, J.J. / Friends, T.J. / Rossi, K.A. / Smallheer, J.M. / Wang, C. / Sun, Z. / Corte, J.R. / Fang, T. / Wong, P.C. / Rendina, A.A. / Barbera, F.A. / Bozarth, J.M. / Luettgen, J.M. / ...Authors: Hangeland, J.J. / Friends, T.J. / Rossi, K.A. / Smallheer, J.M. / Wang, C. / Sun, Z. / Corte, J.R. / Fang, T. / Wong, P.C. / Rendina, A.A. / Barbera, F.A. / Bozarth, J.M. / Luettgen, J.M. / Watson, C.A. / Zhang, G. / Wei, A. / Ramamurthy, V. / Morin, P.E. / Bisacchi, G.S. / Subramaniam, S. / Arunachalam, P. / Mathur, A. / Seiffert, D.A. / Wexler, R.R. / Quan, M.L.
History
DepositionNov 13, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 28, 2015Provider: repository / Type: Initial release
Revision 1.1Feb 11, 2015Group: Database references
Revision 1.2Feb 18, 2015Group: Database references
Revision 1.3Aug 29, 2018Group: Data collection / Derived calculations ...Data collection / Derived calculations / Source and taxonomy / Structure summary
Category: entity / entity_src_gen ...entity / entity_src_gen / entity_src_nat / pdbx_struct_assembly / pdbx_struct_oper_list
Item: _entity.src_method / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: COAGULATION FACTOR XI, LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,3856
Polymers27,6001
Non-polymers7855
Water2,414134
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)79.000, 79.000, 106.500
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Components on special symmetry positions
IDModelComponents
11A-302-

SO4

21A-410-

HOH

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Components

#1: Antibody COAGULATION FACTOR XI, LIGHT CHAIN / FXI / Plasma thromboplastin antecedent / PTA


Mass: 27600.342 Da / Num. of mol.: 1 / Fragment: unp residues 388-625 / Mutation: N491G, T493G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F11 / Plasmid: PET14B / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P03951, coagulation factor XIa
#2: Chemical ChemComp-3VM / trans-N-{(1S)-1-[4-(3-amino-2H-indazol-6-yl)pyridin-2-yl]-2-phenylethyl}-4-(aminomethyl)cyclohexanecarboxamide


Mass: 468.593 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C28H32N6O
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 134 / Source method: isolated from a natural source / Formula: H2O

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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: 3.48 Å3/Da / Density % sol: 64.61 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 100 MM SODIUM ACETATE, PH 4.6, 26%(w/v) MEPEG2000, 200 MM AMMONIUM SULFATE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Aug 23, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 12246 / % possible obs: 99.8 % / Observed criterion σ(I): 0 / Redundancy: 9.5 % / Biso Wilson estimate: 44.1 Å2 / Rmerge(I) obs: 0.111 / Net I/σ(I): 19.1
Reflection shellResolution: 2.6→2.69 Å / Redundancy: 7.3 % / Rmerge(I) obs: 0.343 / Mean I/σ(I) obs: 4.3 / Rejects: 0 / % possible all: 98.7

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Processing

Software
NameVersionClassification
BUSTER-TNTBUSTER 2.9.4refinement
PDB_EXTRACT3.15data extraction
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: FACTOR XIA DOUBLE MUTANT

Resolution: 2.6→42.02 Å / Cor.coef. Fo:Fc: 0.924 / Cor.coef. Fo:Fc free: 0.8876 / SU R Cruickshank DPI: 0.328 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.368 / SU Rfree Blow DPI: 0.246 / SU Rfree Cruickshank DPI: 0.241
RfactorNum. reflection% reflectionSelection details
Rfree0.2261 1011 8.27 %RANDOM
Rwork0.1764 ---
obs0.1805 12220 99.65 %-
Displacement parametersBiso max: 111.5 Å2 / Biso mean: 22.37 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1--4.453 Å20 Å20 Å2
2---4.453 Å20 Å2
3---8.906 Å2
Refine analyzeLuzzati coordinate error obs: 0.265 Å
Refinement stepCycle: final / Resolution: 2.6→42.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1867 0 53 134 2054
Biso mean--21.65 23.7 -
Num. residues----238
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d665SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes43HARMONIC2
X-RAY DIFFRACTIONt_gen_planes282HARMONIC5
X-RAY DIFFRACTIONt_it1969HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion249SEMIHARMONIC5
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_contact2213SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1969HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2671HARMONIC21.22
X-RAY DIFFRACTIONt_omega_torsion3.35
X-RAY DIFFRACTIONt_other_torsion19.84
LS refinement shellResolution: 2.6→2.85 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2964 251 8.86 %
Rwork0.1975 2581 -
all0.2058 2832 -
obs--99.65 %

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