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- PDB-4bti: factor Xa in complex with the dual thrombin-FXa inhibitor 58. -

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Basic information

Entry
Database: PDB / ID: 4bti
Titlefactor Xa in complex with the dual thrombin-FXa inhibitor 58.
Components
  • COAGULATION FACTOR X HEAVY CHAINFactor X
  • COAGULATION FACTOR X LIGHT CHAINFactor X
KeywordsHYDROLASE / SAR107375 / FACTOR XA INHIBITOR / THROMBIN INHIBITOR / CHLOROTHIOPHENE P1 FRAGMENT / S3 SUBSITE / MICROSOMES STABILITY / ORAL ANTITHROMBOTIC / DUAL INHIBITOR / IV ANTITHROMBOTIC
Function / homology
Function and homology information


coagulation factor Xa / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / Extrinsic Pathway of Fibrin Clot Formation / positive regulation of TOR signaling / Gamma-carboxylation of protein precursors / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins ...coagulation factor Xa / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / Extrinsic Pathway of Fibrin Clot Formation / positive regulation of TOR signaling / Gamma-carboxylation of protein precursors / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / Intrinsic Pathway of Fibrin Clot Formation / phospholipid binding / Golgi lumen / blood coagulation / positive regulation of cell migration / endoplasmic reticulum lumen / external side of plasma membrane / serine-type endopeptidase activity / calcium ion binding / proteolysis / extracellular space / extracellular region / plasma membrane
Similarity search - Function
Peptidase S1A, coagulation factor VII/IX/X/C/Z / Coagulation factor-like, Gla domain superfamily / Coagulation Factor Xa inhibitory site / Laminin / Laminin / EGF-type aspartate/asparagine hydroxylation site / EGF-like domain / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. ...Peptidase S1A, coagulation factor VII/IX/X/C/Z / Coagulation factor-like, Gla domain superfamily / Coagulation Factor Xa inhibitory site / Laminin / Laminin / EGF-type aspartate/asparagine hydroxylation site / EGF-like domain / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain superfamily / Vitamin K-dependent carboxylation domain. / Gla domain profile. / Domain containing Gla (gamma-carboxyglutamate) residues. / Epidermal growth factor-like domain. / EGF-like domain profile. / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain / Ribbon / 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 domain profile. / Serine proteases, trypsin family, serine active site. / 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-7R9 / Coagulation factor X
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsMeneyrol, J. / Follmann, M. / Lassalle, G. / Wehner, V. / Barre, G. / Rousseaux, T. / Altenburger, J.M. / Petit, F. / Bocskei, Z. / Stehlin-Gaon, C. ...Meneyrol, J. / Follmann, M. / Lassalle, G. / Wehner, V. / Barre, G. / Rousseaux, T. / Altenburger, J.M. / Petit, F. / Bocskei, Z. / Stehlin-Gaon, C. / Schreuder, H. / Alet, N. / Herault, J.-P. / Millet, L. / Dol, F. / Hasbrand, C. / Schaeffer, P. / Sadoun, F. / Klieber, S. / Briot, C. / Bono, F. / Herbert, J.-M.
CitationJournal: J.Med.Chem. / Year: 2013
Title: 5-Chlorothiophene-2-Carboxylic Acid [(S)-2-[2-Methyl-3-(2-Oxopyrrolidin-1-Yl)Benzenesulfonylamino]-3-(4-Methylpiperazin-1-Yl)-3-Oxopropyl]Amide (Sar107375), a Selective and Potent Orally ...Title: 5-Chlorothiophene-2-Carboxylic Acid [(S)-2-[2-Methyl-3-(2-Oxopyrrolidin-1-Yl)Benzenesulfonylamino]-3-(4-Methylpiperazin-1-Yl)-3-Oxopropyl]Amide (Sar107375), a Selective and Potent Orally Active Dual Thrombin and Factor Xa Inhibitor.
Authors: Meneyrol, J. / Follmann, M. / Lassalle, G. / Wehner, V. / Barre, G. / Rousseaux, T. / Altenburger, J. / Petit, F. / Bocskei, Z. / Schreuder, H. / Alet, N. / Herault, J. / Millet, L. / Dol, F. ...Authors: Meneyrol, J. / Follmann, M. / Lassalle, G. / Wehner, V. / Barre, G. / Rousseaux, T. / Altenburger, J. / Petit, F. / Bocskei, Z. / Schreuder, H. / Alet, N. / Herault, J. / Millet, L. / Dol, F. / Florian, P. / Schaeffer, P. / Sadoun, F. / Klieber, S. / Briot, C. / Bono, F. / Herbert, J.
History
DepositionJun 18, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 25, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2014Group: Database references
Revision 1.2May 8, 2019Group: Data collection / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "BB" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "BB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL. SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "FB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: COAGULATION FACTOR X HEAVY CHAIN
B: COAGULATION FACTOR X LIGHT CHAIN
E: COAGULATION FACTOR X HEAVY CHAIN
F: COAGULATION FACTOR X LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,5458
Polymers78,1694
Non-polymers1,3764
Water10,971609
1
E: COAGULATION FACTOR X HEAVY CHAIN
F: COAGULATION FACTOR X LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,7734
Polymers39,0842
Non-polymers6882
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1700 Å2
ΔGint-9.4 kcal/mol
Surface area13470 Å2
MethodPISA
2
A: COAGULATION FACTOR X HEAVY CHAIN
B: COAGULATION FACTOR X LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,7734
Polymers39,0842
Non-polymers6882
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1820 Å2
ΔGint-21.4 kcal/mol
Surface area13390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.650, 55.650, 173.160
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number145
Space group name H-MP32
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21E
12B
22F

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010A1A - 50
2010E1A - 50
1020B16 - 244
2020F16 - 244

NCS ensembles :
ID
1
2

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Components

#1: Protein COAGULATION FACTOR X HEAVY CHAIN / Factor X / STUART FACTOR / STUART-PROWER FACTOR ACTIVATED FACTOR XA HEAVY CHAIN


Mass: 10533.713 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Details: ISOLATED FROM HUMAN SERUM / Source: (natural) HOMO SAPIENS (human) / Tissue: BLOOD / References: UniProt: P00742, coagulation factor Xa
#2: Protein COAGULATION FACTOR X LIGHT CHAIN / Factor X / STUART FACTOR / STUART-PROWER FACTOR / FACTOR X HEAVY CHAIN


Mass: 28550.596 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Details: ISOLATED FROM HUMAN SERUM / Source: (natural) HOMO SAPIENS (human) / Tissue: BLOOD / References: UniProt: P00742, coagulation factor Xa
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-7R9 / 5-Chloro-thiophene-2-carboxylic acid [(S)-2-[2-difluoromethoxy-3-(2-oxo-piperidin-1-yl)-benzenesulfonylamino]-3-((S)-3-dimethylamino-pyrrolidin-1-yl)-3-oxo-propyl]-amide


Mass: 648.142 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H32ClF2N5O6S2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 609 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsDES-GLA

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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: 2.4 Å3/Da / Density % sol: 49 % / Description: NONE
Crystal growMethod: vapor diffusion, hanging drop / pH: 5.7
Details: PROTEIN SOLUTION: 8 MG/ML DESGLA FACTOR XA, 5 MM MES (PH 6.0), 5 MM CACL2, 100 MM BENZAMIDINE. RESERVOIR SOLUTION: 18-20% PEG600, 50 MM MES (PH 5.7). HANGING DROP SETUP.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8726
DetectorDate: Apr 18, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.619
11K, H, -L20.381
ReflectionResolution: 2.29→47.98 Å / Num. obs: 26327 / % possible obs: 98.5 % / Observed criterion σ(I): -3 / Redundancy: 2.9 % / Rmerge(I) obs: 0.14 / Net I/σ(I): 6.7
Reflection shellResolution: 2.29→2.36 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.51 / Mean I/σ(I) obs: 2.6 / % possible all: 94.7

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: IN-HOUSE FACTOR XA STRUCTURE

Resolution: 2.3→36.99 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.9 / SU B: 8.394 / SU ML: 0.134 / Cross valid method: THROUGHOUT / ESU R: 0.091 / ESU R Free: 0.051 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22434 1207 4.6 %RANDOM
Rwork0.166 ---
obs0.16862 25117 98.46 %-
Solvent computationIon probe radii: 0.7 Å / Shrinkage radii: 0.7 Å / VDW probe radii: 1 Å / Solvent model: MASK
Refinement stepCycle: LAST / Resolution: 2.3→36.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4498 0 86 609 5193
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0194692
X-RAY DIFFRACTIONr_bond_other_d0.0020.024366
X-RAY DIFFRACTIONr_angle_refined_deg1.0511.9686344
X-RAY DIFFRACTIONr_angle_other_deg0.7963.0099954
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4675570
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.43623.981216
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.28515804
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8011532
X-RAY DIFFRACTIONr_chiral_restr0.0580.2674
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025304
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021076
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.1 Å / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumber
11A2499
12E2499
21B13902
22F13902
LS refinement shellResolution: 2.297→2.356 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.302 88 -
Rwork0.215 1721 -
obs--93.54 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
15.4152-0.5966-1.30763.92890.89684.32490.07040.03120.1672-0.1019-0.0148-0.2684-0.0204-0.0809-0.05560.1170.0137-0.03240.15370.01760.039223.141-11.911-10.552
21.74630.49650.50521.72880.38751.2340.02110.04430.0375-0.0502-0.0165-0.0091-0.0272-0.0228-0.00460.0920.01910.01430.11330.00450.0030.45-4.665-14.23
35.5664-0.6182-0.21195.49010.06341.88880.0339-0.36660.30610.2516-0.07380.2011-0.12050.10320.03990.19280.0532-0.05050.20830.00420.065914.9193.559-47.356
41.48020.0332-0.01321.7721-0.61851.44310.00350.0203-0.0523-0.05910.0089-0.04020.0358-0.0075-0.01250.1164-0.006-0.00010.1237-0.01920.00632.37-12.903-43.835
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 50
2X-RAY DIFFRACTION2B16 - 244
3X-RAY DIFFRACTION3E1 - 50
4X-RAY DIFFRACTION4F16 - 244

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