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- PDB-4x6o: FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl (4-{4-chloro-2-[(... -

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Basic information

Entry
Database: PDB / ID: 4x6o
TitleFACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl (4-{4-chloro-2-[(1S)-1-({3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]propanoyl}amino)-2-phenylethyl]-1H-imidazol-5-yl}phenyl)carbamate
ComponentsCoagulation factor XI, light chain
Keywordshydrolase/hydrolase inhibitor / 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-3Y4 / Coagulation factor XI
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsWei, A.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties.
Authors: Pinto, D.J. / Smallheer, J.M. / Corte, J.R. / Austin, E.J. / Wang, C. / Fang, T. / Smith, L.M. / Rossi, K.A. / Rendina, A.R. / Bozarth, J.M. / Zhang, G. / Wei, A. / Ramamurthy, V. / Sheriff, ...Authors: Pinto, D.J. / Smallheer, J.M. / Corte, J.R. / Austin, E.J. / Wang, C. / Fang, T. / Smith, L.M. / Rossi, K.A. / Rendina, A.R. / Bozarth, J.M. / Zhang, G. / Wei, A. / Ramamurthy, V. / Sheriff, S. / Myers, J.E. / Morin, P.E. / Luettgen, J.M. / Seiffert, D.A. / Quan, M.L. / Wexler, R.R.
#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.
#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.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.
#3: 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.
History
DepositionDec 8, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 18, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 18, 2015Group: Database references
Revision 1.2Apr 1, 2015Group: Database references

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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)28,95713
Polymers27,6001
Non-polymers1,35612
Water3,729207
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)78.700, 78.700, 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-303-

SO4

21A-410-

HOH

Detailschain A

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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 / Mutation: N113G, T115G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F11 / Plasmid: PET14B / Production host: Escherichia coli (E. coli) / References: UniProt: P03951, coagulation factor XIa
#2: Chemical ChemComp-3Y4 / methyl (4-{4-chloro-2-[(1S)-1-({3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]propanoyl}amino)-2-phenylethyl]-1H-imidazol-5-yl}phenyl)carbamate


Mass: 605.475 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H26Cl2N8O3
#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.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 207 / 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: 3.55 Å3/Da / Density % sol: 65.35 %
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: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Aug 24, 2006 / Details: MICROMAX CONFOCAL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 22771 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 10.2 % / Biso Wilson estimate: 27.25 Å2 / Rmerge(I) obs: 0.146 / Net I/σ(I): 18
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 7.6 % / Rmerge(I) obs: 0.477 / Mean I/σ(I) obs: 3.7 / Rejects: 0 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER-TNTBUSTER 2.9.6refinement
PDB_EXTRACT3.15data extraction
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: FACTOR XIA DOUBLE MUTANT

Resolution: 2.1→26.33 Å / Cor.coef. Fo:Fc: 0.9424 / Cor.coef. Fo:Fc free: 0.9186 / SU R Cruickshank DPI: 0.152 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.163 / SU Rfree Blow DPI: 0.152 / SU Rfree Cruickshank DPI: 0.147
RfactorNum. reflection% reflectionSelection details
Rfree0.2277 497 2.19 %RANDOM
Rwork0.1851 ---
obs0.186 22691 99.72 %-
Displacement parametersBiso max: 104.84 Å2 / Biso mean: 27.25 Å2 / Biso min: 11.33 Å2
Baniso -1Baniso -2Baniso -3
1--3.2895 Å20 Å20 Å2
2---3.2895 Å20 Å2
3---6.5789 Å2
Refine analyzeLuzzati coordinate error obs: 0.228 Å
Refinement stepCycle: final / Resolution: 2.1→26.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1859 0 88 207 2154
Biso mean--30.36 36.56 -
Num. residues----238
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d679SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes41HARMONIC2
X-RAY DIFFRACTIONt_gen_planes322HARMONIC5
X-RAY DIFFRACTIONt_it1996HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion250SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance2HARMONIC1
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2407SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1996HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2696HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion3.84
X-RAY DIFFRACTIONt_other_torsion15.85
LS refinement shellResolution: 2.1→2.2 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.194 66 2.22 %
Rwork0.182 2903 -
all0.1823 2969 -
obs--99.72 %

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