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- PDB-4ty7: Factor XIa in complex with the inhibitor (2S)-6-amino-N-{(1S)-1-[... -

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Basic information

Entry
Database: PDB / ID: 4ty7
TitleFactor XIa in complex with the inhibitor (2S)-6-amino-N-{(1S)-1-[4-(3-amino-2H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenylethyl}-2-ethylhexanamide
ComponentsCoagulation factor XIFactor XI
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 / membrane / identical protein binding / 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-39F / Coagulation factor XI
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.09 Å
AuthorsWei, A.
Citation
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.R. / 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.R. / 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.
#1: Journal: J.Med.Chem. / Year: 2014
Title: Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors.
Authors: Quan, M.L. / Wong, P.C. / Wang, C. / Woerner, F. / Smallheer, J.M. / Barbera, F.A. / Bozarth, 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. / Wang, C. / Woerner, F. / Smallheer, J.M. / Barbera, F.A. / Bozarth, 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. / Seiffert, D. / Wexler, R.R.
History
DepositionJul 8, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 3, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 17, 2014Group: Database references
Revision 1.2Feb 25, 2015Group: Derived calculations
Revision 2.0Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Non-polymer description / Other / Refinement description / Source and taxonomy / Structure summary
Category: citation / entity ...citation / entity / entity_src_gen / pdbx_database_status / pdbx_struct_oper_list / software
Item: _chem_comp.formula / _chem_comp.name ..._chem_comp.formula / _chem_comp.name / _citation.journal_id_CSD / _entity.formula_weight / _entity.pdbx_description / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation
Revision 2.1Dec 27, 2023Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.2Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)28,71911
Polymers27,6001
Non-polymers1,11910
Water3,981221
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1620 Å2
ΔGint-12 kcal/mol
Surface area11290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)79.100, 79.100, 106.300
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

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Components

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


Mass: 27600.342 Da / Num. of mol.: 1 / Fragment: Light chain (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 (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P03951, coagulation factor XIa
#2: Chemical ChemComp-39F / trans-N-{(1S)-1-[4-(3-amino-2H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenylethyl}-4-(aminomethyl)cyclohexane-1-carboxamide


Mass: 492.016 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H30ClN7O
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 221 / 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: 3.59 Å3/Da / Density % sol: 65.7 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.6
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: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Jan 6, 2005 / Details: MICROMAX CONFOCAL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.09→50 Å / Num. obs: 23320 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 10.3 % / Biso Wilson estimate: 26.15 Å2 / Rmerge(I) obs: 0.086 / Net I/σ(I): 30.3
Reflection shellResolution: 2.09→2.16 Å / Redundancy: 7.3 % / Rmerge(I) obs: 0.285 / Mean I/σ(I) obs: 6.4 / Rejects: 0 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER-TNTBUSTER 2.9.4refinement
PDB_EXTRACT3.14data extraction
Cootmodel building
BUSTER2.9.4refinement
AMoREphasing
HKL-2000(DENZO)data reduction
HKL-2000(SCALEPACK)data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: FACTOR XIA DOUBLE MUTANT

Resolution: 2.09→32.6 Å / Cor.coef. Fo:Fc: 0.9384 / Cor.coef. Fo:Fc free: 0.9198 / SU R Cruickshank DPI: 0.142 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.153 / SU Rfree Blow DPI: 0.135 / SU Rfree Cruickshank DPI: 0.13
RfactorNum. reflection% reflectionSelection details
Rfree0.2059 1035 4.45 %RANDOM
Rwork0.1786 ---
obs0.1798 23284 99.89 %-
Displacement parametersBiso max: 96.32 Å2 / Biso mean: 26.5 Å2 / Biso min: 11 Å2
Baniso -1Baniso -2Baniso -3
1--3.8054 Å20 Å20 Å2
2---3.8054 Å20 Å2
3---7.6108 Å2
Refine analyzeLuzzati coordinate error obs: 0.203 Å
Refinement stepCycle: final / Resolution: 2.09→32.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1853 0 73 221 2147
Biso mean--31.72 36.24 -
Num. residues----238
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d659SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes41HARMONIC2
X-RAY DIFFRACTIONt_gen_planes281HARMONIC5
X-RAY DIFFRACTIONt_it1970HARMONIC20
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_contact2372SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1970HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2665HARMONIC21.04
X-RAY DIFFRACTIONt_omega_torsion3.87
X-RAY DIFFRACTIONt_other_torsion16.01
LS refinement shellResolution: 2.09→2.18 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.217 123 4.44 %
Rwork0.1687 2646 -
all0.1707 2769 -
obs--99.89 %

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