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- PDB-4btt: factor Xa in complex with the dual thrombin-FXa inhibitor 31. -

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Basic information

Entry
Database: PDB / ID: 4btt
Titlefactor Xa in complex with the dual thrombin-FXa inhibitor 31.
Components
  • COAGULATION FACTOR X
  • COAGULATION FACTOR X LIGHT CHAIN
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 / Laminin / Laminin / Coagulation Factor Xa inhibitory site / EGF-like domain / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. ...Peptidase S1A, coagulation factor VII/IX/X/C/Z / : / Coagulation factor-like, Gla domain superfamily / Laminin / Laminin / Coagulation Factor Xa inhibitory site / EGF-like domain / EGF-type aspartate/asparagine hydroxylation site / 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 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-VYR / Coagulation factor X
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.59 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 19, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 18, 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
Revision 1.3May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
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 LIGHT CHAIN
B: COAGULATION FACTOR X
E: COAGULATION FACTOR X LIGHT CHAIN
F: COAGULATION FACTOR X
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,5238
Polymers78,1694
Non-polymers1,3544
Water4,035224
1
E: COAGULATION FACTOR X LIGHT CHAIN
F: COAGULATION FACTOR X
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,7624
Polymers39,0842
Non-polymers6772
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2790 Å2
ΔGint-23 kcal/mol
Surface area13830 Å2
MethodPISA
2
A: COAGULATION FACTOR X LIGHT CHAIN
B: COAGULATION FACTOR X
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,7624
Polymers39,0842
Non-polymers6772
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2620 Å2
ΔGint-10.5 kcal/mol
Surface area13830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.210, 56.210, 175.440
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number145
Space group name H-MP32

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Components

#1: Protein COAGULATION FACTOR X LIGHT CHAIN / STUART FACTOR / STUART-PROWER FACTOR / FACTOR X LIGHT CHAIN


Mass: 10533.713 Da / Num. of mol.: 2 / Fragment: LIGHT CHAIN, RESIDUES 84-179 / Source method: isolated from a natural source / Details: DES-GLA DOMAIN / Source: (natural) HOMO SAPIENS (human) / Tissue: SERUM / References: UniProt: P00742, coagulation factor Xa
#2: Protein COAGULATION FACTOR X / STUART FACTOR / STUART-PROWER FACTOR / FACTOR X HEAVY CHAIN


Mass: 28550.596 Da / Num. of mol.: 2 / Fragment: HEAVY CHAIN, RESIDUES 235-488 / Source method: isolated from a natural source / Source: (natural) HOMO SAPIENS (human) / Tissue: SERUM / 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-VYR / N-[(S)-1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(4-methoxy-piperidin-1-yl)-2-oxo-ethyl]-2-ethyl-3-(3-oxo-morpholin-4-yl)-benzenesulfonamide


Mass: 637.167 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H33ClN4O7S2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 224 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Sequence detailsACTIVATED FORM GLA DOMAIN REMOVED WITH CHYMOTRYPSIN

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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: 2.6 Å3/Da / Density % sol: 53.4 % / 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
DetectorType: MARRESEARCH / Detector: CCD / Date: Apr 19, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
ReflectionResolution: 2.59→48.68 Å / Num. obs: 18301 / % possible obs: 94.7 % / Observed criterion σ(I): -3 / Redundancy: 2.6 % / Biso Wilson estimate: 54.82 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 9.1
Reflection shellResolution: 2.59→2.73 Å / Redundancy: 2 % / Rmerge(I) obs: 0.25 / Mean I/σ(I) obs: 2.5 / % possible all: 92.9

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: IN-HOUSE FACTOR XA STRUCTURE

Resolution: 2.59→48.68 Å / Cor.coef. Fo:Fc: 0.9118 / Cor.coef. Fo:Fc free: 0.8749 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.312 / Details: EGF-1 DOMAIN IS DISORDERED
RfactorNum. reflection% reflectionSelection details
Rfree0.2361 848 4.63 %RANDOM
Rwork0.1993 ---
obs0.201 18301 94.73 %-
Displacement parametersBiso mean: 40.79 Å2
Baniso -1Baniso -2Baniso -3
1--3.4912 Å20 Å20 Å2
2---3.4912 Å20 Å2
3---6.9824 Å2
Refine analyzeLuzzati coordinate error obs: 0.323 Å
Refinement stepCycle: LAST / Resolution: 2.59→48.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4469 0 86 224 4779
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0074705HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.956367HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1642SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes122HARMONIC2
X-RAY DIFFRACTIONt_gen_planes681HARMONIC5
X-RAY DIFFRACTIONt_it4705HARMONIC20
X-RAY DIFFRACTIONt_nbd3SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion1.64
X-RAY DIFFRACTIONt_other_torsion18.56
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion597SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies4HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4997SEMIHARMONIC4
LS refinement shellResolution: 2.59→2.75 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2881 155 5.34 %
Rwork0.2359 2746 -
all0.239 2901 -
obs--94.73 %

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