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- PDB-4y8x: Factor XIa in complex with the inhibitor methyl (4-{4-chloro-2-[(... -

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Entry
Database: PDB / ID: 4y8x
TitleFactor XIa in complex with the inhibitor methyl (4-{4-chloro-2-[(1S)-1-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-2-phenylethyl]-1H-imidazol-5-yl}phenyl)carbamate
ComponentsCoagulation factor XIa
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 / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family ...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 / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / 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-4GR / Coagulation factor XI
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsSheriff, S.
Citation
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.
#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.
History
DepositionFeb 16, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 27, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 18, 2018Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Source and taxonomy / Structure summary
Category: chem_comp / citation ...chem_comp / citation / citation_author / entity / entity_src_gen / pdbx_entity_nonpoly / pdbx_struct_assembly / pdbx_struct_assembly_prop / pdbx_struct_oper_list
Item: _chem_comp.name / _citation.journal_abbrev ..._chem_comp.name / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name / _entity.pdbx_description / _entity_src_gen.pdbx_alt_source_flag / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Coagulation factor XIa
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,95513
Polymers27,6001
Non-polymers1,35412
Water3,873215
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2080 Å2
ΔGint-2 kcal/mol
Surface area11170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.780, 78.780, 106.320
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-471-

HOH

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Components

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


Mass: 27600.342 Da / Num. of mol.: 1 / Fragment: light 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 BL21(DE3) (bacteria) / References: UniProt: P03951, coagulation factor XIa
#2: Chemical ChemComp-4GR / methyl (4-{4-chloro-2-[(1S)-1-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-2-phenylethyl]-1H-imidazol-5-yl}phenyl)carbamate


Mass: 603.459 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H24Cl2N8O3
#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.: 215 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 65.73 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 100 mM sodium acetate, pH 4.6, 26% w/v MEPEG2000, 200 mM ammonium sulfate (crystals were grown at pH4.6 and transferred to pH 7 prior to soaking with compound)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 18, 2010
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→106.32 Å / Num. obs: 30451 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 12.3 % / Biso Wilson estimate: 23.83 Å2 / Rmerge(I) obs: 0.072 / Net I/σ(I): 27.5
Reflection shellResolution: 1.9→2.01 Å / Redundancy: 12.7 % / Rmerge(I) obs: 0.399 / Mean I/σ(I) obs: 8.3 / Rejects: 0 / % possible all: 99.9

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Processing

Software
NameVersionClassification
BUSTER-TNTBUSTER 2.11.6refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4TY7

4ty7


Resolution: 1.9→57.42 Å / Cor.coef. Fo:Fc: 0.9498 / Cor.coef. Fo:Fc free: 0.9497 / SU R Cruickshank DPI: 0.095 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.1 / SU Rfree Blow DPI: 0.086 / SU Rfree Cruickshank DPI: 0.083
RfactorNum. reflection% reflectionSelection details
Rfree0.1644 736 2.42 %RANDOM
Rwork0.1575 ---
obs0.1577 30421 99.28 %-
Displacement parametersBiso max: 96.49 Å2 / Biso mean: 27.12 Å2 / Biso min: 11.22 Å2
Baniso -1Baniso -2Baniso -3
1--3.3377 Å20 Å20 Å2
2---3.3377 Å20 Å2
3---6.6755 Å2
Refine analyzeLuzzati coordinate error obs: 0.157 Å
Refinement stepCycle: final / Resolution: 1.9→57.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1853 0 88 215 2156
Biso mean--34.76 38.81 -
Num. residues----238
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d691SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes41HARMONIC2
X-RAY DIFFRACTIONt_gen_planes352HARMONIC5
X-RAY DIFFRACTIONt_it2032HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion256SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance6HARMONIC1
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2480SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2032HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2770HARMONIC21.03
X-RAY DIFFRACTIONt_omega_torsion3.95
X-RAY DIFFRACTIONt_other_torsion14.45
LS refinement shellResolution: 1.9→1.97 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.1459 58 2.1 %
Rwork0.1543 2702 -
all0.1541 2760 -
obs--99.28 %

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