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- PDB-1wu1: Factor Xa in complex with the inhibitor 4-[(5-chloroindol-2-yl)su... -

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Basic information

Entry
Database: PDB / ID: 1wu1
TitleFactor Xa in complex with the inhibitor 4-[(5-chloroindol-2-yl)sulfonyl]-2-(2-methylpropyl)-1-[[5-(pyridin-4-yl) pyrimidin-2-yl]carbonyl]piperazine
Components
  • Coagulation factor X, heavy chain
  • Coagulation factor X, light chain
KeywordsHYDROLASE / glycoprotein / serine protease / plasma / blood coagulation factor / protein inhibitor complex / calcium-binding
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 / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Gamma-carboxylation of protein precursors / 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 / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Gamma-carboxylation of protein precursors / 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 1. / EGF-like domain signature 2. / EGF-like domain / Ribbon / 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-D91 / Coagulation factor X
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / RIGID BODY REFINEMENT / Resolution: 2.3 Å
AuthorsSuzuki, M.
Citation
Journal: Bioorg.Med.Chem. / Year: 2005
Title: Design, synthesis, and biological activity of non-basic compounds as factor Xa inhibitors: SAR study of S1 and aryl binding sites
Authors: Komoriya, S. / Haginoya, N. / Kobayashi, S. / Nagata, T. / Mochizuki, A. / Suzuki, M. / Yoshino, T. / Horino, H. / Nagahara, T. / Suzuki, M. / Isobe, Y. / Furugoori, T.
#1: Journal: Proc.Natl.Acad.Sci.Usa / Year: 1998
Title: Structural basis for chemical inhibition of human blood coagulation factor Xa
Authors: Kamata, K. / Kawamoto, H. / Honma, T. / Iwama, T. / Kim, S.H.
#2: Journal: J.Biol.Chem. / Year: 1996
Title: X-ray structure of active site-inhibited clotting factor Xa. Implications for drug design and substrate recognition
Authors: Brandstetter, H. / Kuhne, A. / Bode, W. / Huber, R. / von der Saal, W. / Wirthensohn, K. / Engh, R.A.
#3: Journal: J.Mol.Biol. / Year: 1993
Title: Structure of human des(1-45) factor Xa at 2.2 A resolution
Authors: Padmanabhan, K. / Padmanabhan, K.P. / Tulinsky, A. / Park, C.H. / Bode, W. / Huber, R. / Blankenship, D.T. / Cardin, A.D. / Kisiel, W.
#4: Journal: J.Med.Chem. / Year: 2004
Title: Synthesis and Conformational Analysis of a Non-Amidine Factor Xa Inhibitor That Incorporates 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine as S4 Binding Element
Authors: Haginoya, N. / Kobayashi, S. / Komoriya, S. / Yoshino, T. / Suzuki, M. / Shimada, T. / Watanabe, K. / Hirokawa, Y. / Furugori, T. / Nagahara, T.
History
DepositionNov 29, 2004Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 29, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jun 20, 2012Group: Non-polymer description
Revision 1.4Oct 25, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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_struct_conn_angle.ptnr1_PDB_ins_code / _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_PDB_ins_code / _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.pdbx_ptnr1_PDB_ins_code / _struct_conn.pdbx_ptnr2_PDB_ins_code / _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 1.5Oct 23, 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 X, heavy chain
B: Coagulation factor X, light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,3525
Polymers36,7332
Non-polymers6193
Water1,36976
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.569, 72.487, 79.020
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Coagulation factor X, heavy chain / Stuart factor / Stuart-Prower factor


Mass: 26346.000 Da / Num. of mol.: 1 / Fragment: RESIDUES 16-243 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00742, coagulation factor Xa
#2: Protein Coagulation factor X, light chain / Stuart factor / Stuart-Prower factor


Mass: 10386.538 Da / Num. of mol.: 1 / Fragment: RESIDUES 85-138 / Source method: isolated from a natural source / Details: PROTEOLYTIC CLEAVAGE PRODUCT / Source: (natural) Homo sapiens (human) / 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-D91 / 5-CHLORO-2-({3-ISOBUTYL-4-[(5-PYRIDIN-4-YLPYRIMIDIN-2-YL)CARBONYL]PIPERAZIN-1-YL}SULFONYL)-1H-INDOLE / 4-[(5-CHLOROINDOL-2-YL)SULFONYL]-2-(2-METHYLPROPYL)-1-[[5-(PYRIDIN-4-YL)PYRIMIDIN-2-YL]CARBONYL]PIPERAZINE


Mass: 539.049 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H27ClN6O3S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / 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: 2.2 Å3/Da / Density % sol: 44.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5
Details: PEG6000, NaAcetate, pH 5.00, VAPOR DIFFUSION, HANGING DROP, temperature 293K
Crystal grow
*PLUS
Temperature: 20 ℃ / pH: 5 / Method: vapor diffusion
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetailsChemical formula
15 mMmaleate imidazole1droppH5.0
24 mM1dropCaCl2
310 mMbenzamidine1drop
47.5 mg/mlprotein1drop
515 %PEG60001reservoir
61 mM1reservoirCaCl2
70.3 M1reservoirAcONa
80.1 Mmaleate imidazole1reservoirpH5.0

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Data collection

DiffractionMean temperature: 293 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.542 / Wavelength: 1.542 Å
DetectorType: RIGAKU RAXIS IIC / Detector: IMAGE PLATE / Date: Apr 13, 1999
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.542 Å / Relative weight: 1
ReflectionResolution: 2.3→39.51 Å / Num. obs: 13656 / % possible obs: 90.6 % / Observed criterion σ(I): 0 / Redundancy: 2.9 % / Rmerge(I) obs: 0.064 / Rsym value: 0.338 / Net I/σ(I): 11.7
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 2.89 % / Rmerge(I) obs: 0.338 / Mean I/σ(I) obs: 2.89 / Rsym value: 0.338 / % possible all: 84.3
Reflection
*PLUS
Highest resolution: 2.3 Å / Observed criterion σ(I): 0 / Redundancy: 2.9 %
Reflection shell
*PLUS
% possible obs: 84.3 % / Mean I/σ(I) obs: 2.89

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Processing

Software
NameVersionClassification
d*TREKdata scaling
d*TREKdata reduction
REFMAC5.2.0005refinement
RefinementMethod to determine structure: RIGID BODY REFINEMENT
Starting model: 1FAX

1fax


Resolution: 2.3→25 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.912 / SU B: 6.604 / SU ML: 0.166 / Cross valid method: THROUGHOUT / ESU R: 0.338 / ESU R Free: 0.231 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.23535 697 5.1 %RANDOM
Rwork0.18871 ---
obs0.1913 12933 100 %-
Solvent computationSolvent model: BABINET MODEL PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 45.3 Å2
Baniso -1Baniso -2Baniso -3
1-0.31 Å20 Å20 Å2
2---1.7 Å20 Å2
3---1.39 Å2
Refinement stepCycle: LAST / Resolution: 2.3→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2155 0 35 76 2266
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0222245
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.1161.9623050
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2795285
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.16424.11190
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.21415351
X-RAY DIFFRACTIONr_dihedral_angle_4_deg30.1581510
X-RAY DIFFRACTIONr_chiral_restr0.130.2333
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021702
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.250.21019
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3280.21573
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1830.2156
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined0.2150.26
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2110.221
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1490.212
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_mcbond_it1.931.51439
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.1752.52264
X-RAY DIFFRACTIONr_scbond_it2.6482918
X-RAY DIFFRACTIONr_scangle_it3.9613786
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.38 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.307 65 -
Rwork0.208 1203 -
obs--100 %
Refinement
*PLUS
Highest resolution: 2.3 Å / Lowest resolution: 25 Å / Rfactor Rwork: 0.191
Solvent computation
*PLUS
Displacement parameters
*PLUS
Biso mean: 45.3 Å2
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONr_bond_d0.022
X-RAY DIFFRACTIONr_angle_d
X-RAY DIFFRACTIONr_angle_deg2.12
LS refinement shell
*PLUS
Highest resolution: 2.3 Å / Lowest resolution: 2.38 Å

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