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- PDB-4x6p: FACTOR XIA (PICHIA PASTORIS; C500S [C122S]) IN COMPLEX WITH THE I... -

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Basic information

Entry
Database: PDB / ID: 4x6p
TitleFACTOR XIA (PICHIA PASTORIS; C500S [C122S]) IN COMPLEX WITH THE INHIBITOR (2E)-N-{(1S)-1-[4-(3-amino-1H-indazol-6-yl)-1H-imidazol-2-yl]-2-phenylethyl}-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enamide
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 / 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-3YU / CITRIC ACID / Coagulation factor XI
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.93 Å
AuthorsSheriff, S.
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
Revision 1.3Jul 29, 2020Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Source and taxonomy / Structure summary
Category: chem_comp / citation ...chem_comp / citation / entity / entity_src_gen / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / pdbx_struct_oper_list / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _citation.journal_id_CSD / _entity.pdbx_description / _entity_src_gen.pdbx_alt_source_flag / _pdbx_entity_nonpoly.name / _pdbx_struct_oper_list.symmetry_operation / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.4Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.5Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Coagulation factor XI, light chain
B: Coagulation factor XI, light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,00213
Polymers53,7132
Non-polymers2,28911
Water5,513306
1
A: Coagulation factor XI, light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,9135
Polymers26,8561
Non-polymers1,0564
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Coagulation factor XI, light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,0898
Polymers26,8561
Non-polymers1,2337
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)77.774, 82.549, 154.739
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Detailschain A

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Components

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Protein / Sugars , 2 types, 4 molecules AB

#1: Protein Coagulation factor XI, light chain / FXI / Plasma thromboplastin antecedent / PTA


Mass: 26856.496 Da / Num. of mol.: 2 / Mutation: C500S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F11 / Plasmid: pPICZalphaA / Production host: Komagataella pastoris (fungus) / Strain (production host): SMD1168H / References: UniProt: P03951, coagulation factor XIa
#2: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 4 types, 315 molecules

#3: Chemical ChemComp-3YU / (2E)-N-{(1S)-1-[4-(3-amino-1H-indazol-6-yl)-1H-imidazol-2-yl]-2-phenylethyl}-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enamide


Mass: 551.002 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H23ClN10O
#4: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 306 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.31 Å3/Da / Density % sol: 46.8 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5 / Details: 100 MM SODIUM CITRATE, PH 5.0, 36%(w/v) PEG4000

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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: Mar 27, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.93→41.27 Å / Num. obs: 38006 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 6.6 % / Biso Wilson estimate: 23.45 Å2 / Rmerge(I) obs: 0.093 / Net I/σ(I): 14.5
Reflection shellResolution: 1.93→2.03 Å / Redundancy: 6.5 % / Rmerge(I) obs: 0.517 / Mean I/σ(I) obs: 3.3 / % possible all: 99.9

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
PDB_EXTRACT3.15data extraction
PHASERphasing
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3SOR

3sor


Resolution: 1.93→27.47 Å / Cor.coef. Fo:Fc: 0.9528 / Cor.coef. Fo:Fc free: 0.9339 / SU R Cruickshank DPI: 0.142 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.147 / SU Rfree Blow DPI: 0.128 / SU Rfree Cruickshank DPI: 0.126
RfactorNum. reflection% reflectionSelection details
Rfree0.1965 1893 5.01 %RANDOM
Rwork0.164 ---
obs0.1656 37771 99.87 %-
Displacement parametersBiso mean: 24.3 Å2
Baniso -1Baniso -2Baniso -3
1-1.6831 Å20 Å20 Å2
2---1.6449 Å20 Å2
3----0.0382 Å2
Refine analyzeLuzzati coordinate error obs: 0.171 Å
Refinement stepCycle: LAST / Resolution: 1.93→27.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3732 0 157 306 4195
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014049HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.055550HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1378SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes85HARMONIC2
X-RAY DIFFRACTIONt_gen_planes719HARMONIC5
X-RAY DIFFRACTIONt_it4049HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.95
X-RAY DIFFRACTIONt_other_torsion14.34
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion523SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance4HARMONIC1
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4712SEMIHARMONIC4
LS refinement shellResolution: 1.93→1.98 Å / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.2324 144 4.94 %
Rwork0.1865 2773 -
all0.1887 2917 -
obs--99.87 %

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