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- PDB-1fjs: CRYSTAL STRUCTURE OF THE INHIBITOR ZK-807834 (CI-1031) COMPLEXED ... -

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Entry
Database: PDB / ID: 1fjs
TitleCRYSTAL STRUCTURE OF THE INHIBITOR ZK-807834 (CI-1031) COMPLEXED WITH FACTOR XA
Components(COAGULATION FACTOR ...) x 2
KeywordsBLOOD CLOTTING / Protein Inhibitor Complex / Coagulation Cofactor / Protease
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 leukocyte chemotaxis / 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 ...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 leukocyte chemotaxis / 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 / Coagulation Factor Xa inhibitory site / Laminin / 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. ...Peptidase S1A, coagulation factor VII/IX/X/C/Z / Coagulation factor-like, Gla domain superfamily / Laminin / Coagulation Factor Xa inhibitory site / Laminin / 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 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-Z34 / Coagulation factor X
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / DIRECT REPLACEMENT / Resolution: 1.92 Å
AuthorsAdler, M. / Whitlow, M.
Citation
Journal: Biochemistry / Year: 2000
Title: Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa.
Authors: Adler, M. / Davey, D.D. / Phillips, G.B. / Kim, S.H. / Jancarik, J. / Rumennik, G. / Light, D.R. / Whitlow, M.
#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: Acta Crystallogr.,Sect.D / Year: 1999
Title: Crystallographic analysis of potent and selective factor Xa inhibitors complexed to bovine trypsin
Authors: Whitlow, M. / Arnaiz, D.O. / Buckman, B.O. / al., et
#4: Journal: J.Med.Chem. / Year: 1998
Title: Discovery of N-[2-[5-[Amino(imino)methyl]-2-hydroxyphenoxy]-3, 5-difluoro-6-[3-(4, 5-dihydro-1-methyl-1H-imidazol-2-yl)phenoxy]pyridin-4-yl]-N-methylgl y cine (ZK-807834): a potent, selective, ...Title: Discovery of N-[2-[5-[Amino(imino)methyl]-2-hydroxyphenoxy]-3, 5-difluoro-6-[3-(4, 5-dihydro-1-methyl-1H-imidazol-2-yl)phenoxy]pyridin-4-yl]-N-methylgl y cine (ZK-807834): a potent, selective, and orally active inhibitor of the blood coagulation enzyme factor Xa
Authors: Phillips, G.B. / Buckman, B.O. / Davey, D.D. / al., et
#5: Journal: J.Med.Chem. / Year: 1999
Title: Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors
Authors: Phillips, G.B. / Davey, D.D. / Eagen, K.A. / al., et
History
DepositionAug 8, 2000Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 4, 2000Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Oct 4, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software
Revision 1.4Aug 9, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms / 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_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 1.5Mar 13, 2024Group: Source and taxonomy / Structure summary / Category: entity / pdbx_entity_src_syn / Item: _entity.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: COAGULATION FACTOR XA
L: COAGULATION FACTOR XA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,19111
Polymers32,0362
Non-polymers1,1559
Water2,936163
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4400 Å2
ΔGint-37 kcal/mol
Surface area12690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.77, 71.96, 80.23
Angle α, β, γ (deg.)90., 90., 90.
Int Tables number19
Space group name H-MP212121

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Components

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COAGULATION FACTOR ... , 2 types, 2 molecules AL

#1: Protein COAGULATION FACTOR XA


Mass: 26447.104 Da / Num. of mol.: 1 / Fragment: HEAVY CHAIN, CATALYTIC DOMAIN / Source method: isolated from a natural source / Details: EXTRACTED FROM BLOOD / Source: (natural) Homo sapiens (human) / References: UniProt: P00742, coagulation factor Xa
#2: Protein COAGULATION FACTOR XA


Mass: 5589.234 Da / Num. of mol.: 1 / Fragment: LIGHT CHAIN, EPIDERMAL GROWTH FACTOR LIKE DOMAIN / Source method: isolated from a natural source / Details: EXTRACTED FROM BLOOD / Source: (natural) Homo sapiens (human) / References: UniProt: P00742, coagulation factor Xa

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Non-polymers , 5 types, 172 molecules

#3: Chemical ChemComp-CA / CALCIUM ION / SYNTHETIC FACTOR XA INHIBITOR


Mass: 40.078 Da / Num. of mol.: 1 / Fragment: SYNTHETIC FACTOR XA INHIBITOR / Source method: obtained synthetically / Formula: Ca / Details: Berlex Biosciences
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-Z34 / N-[2-[5-[AMINO(IMINO)METHYL]-2-HYDROXYPHENOXY]-3,5-DIFLUORO-6-[3-(4,5-DIHYDRO-1-METHYL-1H-IMIDAZOL-2-YL)PHENOXY]PYRIDIN-4-YL]-N-METHYLGLYCINE


Mass: 526.492 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H24F2N6O5
#6: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 163 / Source method: isolated from a natural source / Formula: H2O

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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: 2.51 Å3/Da / Density % sol: 51.03 %
Description: 1XKA STRUCTURE WAS SUPERIMPOSED ON 1FAX THEN USED FOR DIRECT REPLACEMENT
Crystal growTemperature: 295 K / Method: vapor diffusion / pH: 8
Details: Drop; 2 microliter, 12 mg/ml Factor Xa, 50 mM Tris pH 8.0, 75 mM NaCl + 2 microlter reservoir: Reservoir; 15-21% PEG-1500 and 10mM CaCl2, VAPOR DIFFUSION, temperature 295K
Crystal grow
*PLUS
Method: vapor diffusion, hanging drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formulaDetails
312 mg/mlprotein1drop
415-21 %PEG15001reservoir
510 mM1reservoirCaCl2
1inhibitor1drop3-fold excess
21dropHCl1 equiv

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 1.033
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Nov 19, 1999
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 1.82→26.1 Å / Num. all: 104166 / Num. obs: 29450 / % possible obs: 99.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.5 % / Biso Wilson estimate: 51.6 Å2 / Rsym value: 0.0557 / Net I/σ(I): 12.6
Reflection shellResolution: 1.82→1.93 Å / Redundancy: 3.1 % / Mean I/σ(I) obs: 1.33 / Num. unique all: 4727 / Rsym value: 0.379 / % possible all: 97.1
Reflection
*PLUS
Highest resolution: 1.92 Å / % possible obs: 99.7 % / Redundancy: 3.6 % / Num. measured all: 104166 / Rmerge(I) obs: 0.054
Reflection shell
*PLUS
Highest resolution: 1.92 Å / Lowest resolution: 2.04 Å / % possible obs: 99.9 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.26 / Mean I/σ(I) obs: 2.3

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Processing

Software
NameVersionClassification
X-GENdata scaling
X-GENdata reduction
X-PLOR3.1model building
X-PLOR3.1refinement
X-PLOR3.1phasing
RefinementMethod to determine structure: DIRECT REPLACEMENT
Starting model: 1XKA

1xka


Resolution: 1.92→8 Å / σ(F): 2 / Stereochemistry target values: Engh and Huber
Details: Final refinement had a 400 to 300 degree simulated annealing, followed by a powell minimization, B factor optimization and a final powell minimization.
RfactorNum. reflection% reflectionSelection details
Rfree0.256 891 4 %random
Rwork0.196 ---
all-24059 --
obs-22885 91.9 %-
Displacement parametersBiso mean: 19.44 Å2
Baniso -1Baniso -2Baniso -3
1-0.136 Å20 Å20 Å2
2--4.32 Å20 Å2
3----4.457 Å2
Refinement stepCycle: LAST / Resolution: 1.92→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2236 0 76 163 2475
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONx_bond_d0.011
X-RAY DIFFRACTIONx_angle_deg1.976
X-RAY DIFFRACTIONx_improper_angle_d1.777
X-RAY DIFFRACTIONx_mcbond_it1.5
X-RAY DIFFRACTIONx_mcangle_it2
X-RAY DIFFRACTIONx_scbond_it2
X-RAY DIFFRACTIONx_scangle_it2.5
LS refinement shellResolution: 1.92→2.01 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.268 109 4.5 %
Rwork0.257 2323 -
obs--79.5 %
Xplor fileSerial no: 1 / Param file: PARHCSDX.PRO,PARAM11.WAT / Topol file: TOPHCSDX.PRO
Software
*PLUS
Name: X-PLOR / Version: 3.1 / Classification: refinement
Refinement
*PLUS
Lowest resolution: 8 Å / σ(F): 2 / % reflection Rfree: 4 % / Rfactor obs: 0.196
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg1.777
X-RAY DIFFRACTIONx_mcbond_it1.5
X-RAY DIFFRACTIONx_scbond_it2
X-RAY DIFFRACTIONx_mcangle_it2
X-RAY DIFFRACTIONx_scangle_it2.5
LS refinement shell
*PLUS
Rfactor Rfree: 0.268 / % reflection Rfree: 4.5 % / Rfactor Rwork: 0.257

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