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- PDB-5q0f: FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl [(4R,5E,8S)-8-({(... -

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Basic information

Entry
Database: PDB / ID: 5q0f
TitleFACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl [(4R,5E,8S)-8-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-4-methyl-2-oxo-1,3,4,7,8,10-hexahydro-2H-12,9-(azeno)-1,10-benzodiazacyclotetradecin-15-yl]carbamate
Components
  • Coagulation factor XI
  • MET-ASP-ASP-ASP-ASP-LYS-MET-ASP-ASN-GLU-CYS-THR-THR-LYS-ILE-LYS-PRO-ARG
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-9FA / Coagulation factor XI
Similarity search - Component
Biological speciesHomo sapiens (human)
HOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.12 Å
AuthorsSheriff, S.
Citation
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.
#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. / Wexler, R.R. / Pinto, D.J.
#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.
History
DepositionMay 1, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 12, 2017Provider: repository / Type: Initial release
Revision 1.1Aug 9, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Feb 21, 2018Group: Structure summary / Category: pdbx_deposit_group / Item: _pdbx_deposit_group.group_type
Revision 1.3Oct 16, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Coagulation factor XI
H: MET-ASP-ASP-ASP-ASP-LYS-MET-ASP-ASN-GLU-CYS-THR-THR-LYS-ILE-LYS-PRO-ARG
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,29917
Polymers29,7602
Non-polymers1,53915
Water3,477193
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area610 Å2
ΔGint-8 kcal/mol
Surface area11200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.600, 78.600, 106.000
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-581-

HOH

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AH

#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: Protein/peptide MET-ASP-ASP-ASP-ASP-LYS-MET-ASP-ASN-GLU-CYS-THR-THR-LYS-ILE-LYS-PRO-ARG


Mass: 2159.419 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) HOMO SAPIENS (human) / References: UniProt: P03951*PLUS

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Non-polymers , 4 types, 208 molecules

#3: Chemical ChemComp-9FA / methyl [(4R,5E,8S)-8-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-4-methyl-2-oxo-1,3,4,7,8,10-hexahydro-2H-12,9-(azeno)-1,10-benzodiazacyclotetradecin-15-yl]carbamate


Mass: 602.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H28ClN9O4
#4: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 193 / 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: 3.18 Å3/Da / Density % sol: 61.27 %
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: Jun 8, 2010 / Details: MICROMAX CONFOCAL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.12→50 Å / Num. obs: 21242 / % possible obs: 96.4 % / Observed criterion σ(I): 0 / Redundancy: 10.7 % / Biso Wilson estimate: 30.39 Å2 / Rsym value: 0.092 / Net I/σ(I): 27.4
Reflection shellResolution: 2.12→2.2 Å / Redundancy: 9.1 % / Mean I/σ(I) obs: 6.3 / Rsym value: 0.33 / Rejects: 0 / % possible all: 81.6

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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: 2.12→34.03 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.945 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.169 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.182 / SU Rfree Blow DPI: 0.142 / SU Rfree Cruickshank DPI: 0.137
RfactorNum. reflection% reflectionSelection details
Rfree0.197 1042 4.96 %RANDOM
Rwork0.185 ---
obs0.186 21028 95.5 %-
Displacement parametersBiso max: 127.61 Å2 / Biso mean: 29.9 Å2 / Biso min: 13.52 Å2
Baniso -1Baniso -2Baniso -3
1--3.4058 Å20 Å20 Å2
2---3.4058 Å20 Å2
3---6.8117 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: final / Resolution: 2.12→34.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1889 0 101 193 2183
Biso mean--35.06 37.87 -
Num. residues----243
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d708SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes42HARMONIC2
X-RAY DIFFRACTIONt_gen_planes342HARMONIC5
X-RAY DIFFRACTIONt_it2077HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion262SEMIHARMONIC5
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_contact2489SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2077HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2826HARMONIC21.03
X-RAY DIFFRACTIONt_omega_torsion3.92
X-RAY DIFFRACTIONt_other_torsion15.81
LS refinement shellResolution: 2.12→2.22 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.309 120 5.01 %
Rwork0.231 2274 -
all0.234 2394 -
obs--83.06 %

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