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- PDB-5qcn: FACTOR XIA IN COMPLEX WITH THE INHIBITOR 4-[[(1~{S})-2-[(~{E})-3-... -

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Entry
Database: PDB / ID: 5qcn
TitleFACTOR XIA IN COMPLEX WITH THE INHIBITOR 4-[[(1~{S})-2-[(~{E})-3-[5-chloranyl-2-(1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enoyl]-5-[(3~{S})-3-ethoxycarbonylpiperidin-1-yl]carbonyl-3,4-dihydro-1~{H}-isoquinolin-1-yl]carbonylamino]benzoic acid
ComponentsCoagulation factor 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 / 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-BVM / Coagulation factor XI
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 Å
AuthorsSheriff, S.
Citation
Journal: J. Med. Chem. / Year: 2017
Title: Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212).
Authors: Pinto, D.J.P. / Orwat, M.J. / Smith, L.M. / Quan, M.L. / Lam, P.Y.S. / Rossi, K.A. / Apedo, A. / Bozarth, J.M. / Wu, Y. / Zheng, J.J. / Xin, B. / Toussaint, N. / Stetsko, P. / Gudmundsson, O. ...Authors: Pinto, D.J.P. / Orwat, M.J. / Smith, L.M. / Quan, M.L. / Lam, P.Y.S. / Rossi, K.A. / Apedo, A. / Bozarth, J.M. / Wu, Y. / Zheng, J.J. / Xin, B. / Toussaint, N. / Stetsko, P. / Gudmundsson, O. / Maxwell, B. / Crain, E.J. / Wong, P.C. / Lou, Z. / Harper, T.W. / Chacko, S.A. / Myers, J.E. / Sheriff, S. / Zhang, H. / Hou, X. / Mathur, A. / Seiffert, D.A. / Wexler, R.R. / Luettgen, J.M. / Ewing, W.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.
#4: 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.
#5: Journal: ACS Med Chem Lett / Year: 2015
Title: Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)-one as the P2' Moiety.
Authors: Hu, Z. / Wong, P.C. / Gilligan, P.J. / Han, W. / Pabbisetty, K.B. / Bozarth, J.M. / Crain, E.J. / Harper, T. / Luettgen, J.M. / Myers, J.E. / Ramamurthy, V. / Rossi, K.A. / Sheriff, S. / ...Authors: Hu, Z. / Wong, P.C. / Gilligan, P.J. / Han, W. / Pabbisetty, K.B. / Bozarth, J.M. / Crain, E.J. / Harper, T. / Luettgen, J.M. / Myers, J.E. / Ramamurthy, V. / Rossi, K.A. / Sheriff, S. / Watson, C.A. / Wei, A. / Zheng, J.J. / Seiffert, D.A. / Wexler, R.R. / Quan, M.L.
#6: Journal: Bioorg. Med. Chem. Lett. / Year: 2016
Title: Novel phenylalanine derived diamides as Factor XIa inhibitors.
Authors: Smith, L.M. / Orwat, M.J. / Hu, Z. / Han, W. / Wang, C. / Rossi, K.A. / Gilligan, P.J. / Pabbisetty, K.B. / Osuna, H. / Corte, J.R. / Rendina, A.R. / Luettgen, J.M. / Wong, P.C. / Narayanan, ...Authors: Smith, L.M. / Orwat, M.J. / Hu, Z. / Han, W. / Wang, C. / Rossi, K.A. / Gilligan, P.J. / Pabbisetty, K.B. / Osuna, H. / Corte, J.R. / Rendina, A.R. / Luettgen, J.M. / Wong, P.C. / Narayanan, R. / Harper, T.W. / Bozarth, J.M. / Crain, E.J. / Wei, A. / Ramamurthy, V. / Morin, P.E. / Xin, B. / Zheng, J. / Seiffert, D.A. / Quan, M.L. / Lam, P.Y.S. / Wexler, R.R. / Pinto, D.J.P.
#7: Journal: Bioorg. Med. Chem. / Year: 2016
Title: Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group.
Authors: Corte, J.R. / Fang, T. / Pinto, D.J. / Orwat, M.J. / Rendina, A.R. / Luettgen, J.M. / Rossi, K.A. / Wei, A. / Ramamurthy, V. / Myers, J.E. / Sheriff, S. / Narayanan, R. / Harper, T.W. / ...Authors: Corte, J.R. / Fang, T. / Pinto, D.J. / Orwat, M.J. / Rendina, A.R. / Luettgen, J.M. / Rossi, K.A. / Wei, A. / Ramamurthy, V. / Myers, J.E. / Sheriff, S. / Narayanan, R. / Harper, T.W. / Zheng, J.J. / Li, Y.X. / Seiffert, D.A. / Wexler, R.R. / Quan, M.L.
#8: Journal: J. Med. Chem. / Year: 2017
Title: Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker.
Authors: Corte, J.R. / Fang, T. / Osuna, H. / Pinto, D.J. / Rossi, K.A. / Myers, J.E. / Sheriff, S. / Lou, Z. / Zheng, J.J. / Harper, T.W. / Bozarth, J.M. / Wu, Y. / Luettgen, J.M. / Seiffert, D.A. / ...Authors: Corte, J.R. / Fang, T. / Osuna, H. / Pinto, D.J. / Rossi, K.A. / Myers, J.E. / Sheriff, S. / Lou, Z. / Zheng, J.J. / Harper, T.W. / Bozarth, J.M. / Wu, Y. / Luettgen, J.M. / Seiffert, D.A. / Decicco, C.P. / Wexler, R.R. / Quan, M.L.
#9: Journal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency.
Authors: Corte, J.R. / Yang, W. / Fang, T. / Wang, Y. / Osuna, H. / Lai, A. / Ewing, W.R. / Rossi, K.A. / Myers, J.E. / Sheriff, S. / Lou, Z. / Zheng, J.J. / Harper, T.W. / Bozarth, J.M. / Wu, Y. / ...Authors: Corte, J.R. / Yang, W. / Fang, T. / Wang, Y. / Osuna, H. / Lai, A. / Ewing, W.R. / Rossi, K.A. / Myers, J.E. / Sheriff, S. / Lou, Z. / Zheng, J.J. / Harper, T.W. / Bozarth, J.M. / Wu, Y. / Luettgen, J.M. / Seiffert, D.A. / Quan, M.L. / Wexler, R.R. / Lam, P.Y.S.
#10: Journal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Macrocyclic factor XIa inhibitors.
Authors: Wang, C. / Corte, J.R. / Rossi, K.A. / Bozarth, J.M. / Wu, Y. / Sheriff, S. / Myers, J.E. / Luettgen, J.M. / Seiffert, D.A. / Wexler, R.R. / Quan, M.L.
History
DepositionAug 10, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 8, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2018Group: 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 1.2Feb 21, 2018Group: Structure summary / Category: pdbx_deposit_group / Item: _pdbx_deposit_group.group_type

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Coagulation factor XI
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,34018
Polymers27,6001
Non-polymers1,73917
Water2,648147
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)78.900, 78.900, 105.200
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 / FXI / Plasma thromboplastin antecedent / PTA


Mass: 27600.342 Da / Num. of mol.: 1 / Fragment: HEAVY CHAIN (UNP residues 388-625)
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-BVM / 4-[[(1~{S})-2-[(~{E})-3-[5-chloranyl-2-(1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enoyl]-5-[(3~{S})-3-ethoxycarbonylpiperidin-1-yl]carbonyl-3,4-dihydro-1~{H}-isoquinolin-1-yl]carbonylamino]benzoic acid


Mass: 712.151 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H34ClN7O7
#3: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 62.068 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 147 / 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: 3.42 Å3/Da / Density % sol: 64.09 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 100 mM sodium acetate, pH 4.6, 25% (w/v) MePEG2000, 200 mM ammonium sulfate, then transferred to 100 mM Tris-HCl, pH 7.0, 25% (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 / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: May 30, 2009 / Details: MICROMAX CONFOCAL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 17253 / % possible obs: 99.5 % / Observed criterion σ(I): 0 / Redundancy: 9.5 % / Biso Wilson estimate: 42.05 Å2 / Rsym value: 0.187 / Net I/σ(I): 10.9
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 9.6 % / Mean I/σ(I) obs: 4.8 / Rsym value: 0.543 / Rejects: 0 / % possible all: 99.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4TY7

4ty7


Resolution: 2.3→23.18 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.913 / SU R Cruickshank DPI: 0.223 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.236 / SU Rfree Blow DPI: 0.202 / SU Rfree Cruickshank DPI: 0.197
RfactorNum. reflection% reflectionSelection details
Rfree0.243 1008 5.91 %RANDOM
Rwork0.193 ---
obs0.195 17059 98.6 %-
Displacement parametersBiso max: 100.63 Å2 / Biso mean: 33.57 Å2 / Biso min: 13.37 Å2
Baniso -1Baniso -2Baniso -3
1--2.7035 Å20 Å20 Å2
2---2.7035 Å20 Å2
3---5.4069 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: final / Resolution: 2.3→23.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1857 0 116 147 2120
Biso mean--43.51 39.37 -
Num. residues----238
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d691SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes42HARMONIC2
X-RAY DIFFRACTIONt_gen_planes336HARMONIC5
X-RAY DIFFRACTIONt_it2045HARMONIC20
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_contact2390SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2045HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2780HARMONIC21.08
X-RAY DIFFRACTIONt_omega_torsion3.58
X-RAY DIFFRACTIONt_other_torsion16.89
LS refinement shellResolution: 2.3→2.44 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2564 167 6.2 %
Rwork0.2239 2527 -
all0.2261 2694 -
obs--98.46 %

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