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- PDB-3kl6: Discovery of Tetrahydropyrimidin-2(1H)-one derivative TAK-442: A ... -

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Basic information

Entry
Database: PDB / ID: 3kl6
TitleDiscovery of Tetrahydropyrimidin-2(1H)-one derivative TAK-442: A potent, selective and orally active factor Xa inhibitor
Components(Coagulation Factor X ...) x 2
KeywordsHYDROLASE / coagulation factor Xa / Blood coagulation / Cleavage on pair of basic residues / Disulfide bond / EGF-like domain / Gamma-carboxyglutamic acid / Glycoprotein / Hydroxylation / Protease / Secreted / Serine protease / Zymogen
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-443 / Coagulation factor X
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 Å
AuthorsAertgeerts, K.
CitationJournal: J.Med.Chem. / Year: 2010
Title: Discovery of a tetrahydropyrimidin-2(1H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor.
Authors: Fujimoto, T. / Imaeda, Y. / Konishi, N. / Hiroe, K. / Kawamura, M. / Textor, G.P. / Aertgeerts, K. / Kubo, K.
History
DepositionNov 6, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 1, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Apr 24, 2013Group: Other
Revision 1.3Sep 6, 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_ref_seq_dif / 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_asym_id / _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.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_PDB_ins_code / _pdbx_struct_conn_angle.ptnr3_auth_asym_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.pdbx_ptnr1_PDB_ins_code / _struct_conn.pdbx_ptnr2_PDB_ins_code / _struct_conn.ptnr1_auth_asym_id / _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_asym_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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)34,23810
Polymers33,3902
Non-polymers8488
Water3,675204
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2470 Å2
ΔGint-32 kcal/mol
Surface area13560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.002, 70.345, 78.546
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Coagulation Factor X ... , 2 types, 2 molecules AB

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


Mass: 27201.061 Da / Num. of mol.: 1 / Fragment: Factor X heavy chain residues 235-475
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F10 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P00742, coagulation factor Xa
#2: Protein Coagulation Factor X light chain / Stuart-Prower factor light chain


Mass: 6188.946 Da / Num. of mol.: 1 / Fragment: Factor X light chain residues 126-179
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F10 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P00742, coagulation factor Xa

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Non-polymers , 4 types, 212 molecules

#3: Chemical ChemComp-443 / 1-(1-{(2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoyl}piperidin-4-yl)tetrahydropyrimidin-2(1H)-one


Mass: 479.977 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H26ClN3O5S
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 204 / 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: 2.03 Å3/Da / Density % sol: 39.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 25.% .PEG 3350, 0.1M .tris pH 8.5 , VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorDetector: CCD / Date: May 19, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.45→50 Å / Num. obs: 48381 / % possible obs: 99.3 % / Observed criterion σ(I): 19.7
Reflection shellResolution: 1.45→1.48 Å / % possible all: 99.7

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Processing

SoftwareName: REFMAC / Version: 5.2.0019 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1EZQ

1ezq


Resolution: 1.45→35.17 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.942 / SU B: 1.959 / SU ML: 0.04 / Cross valid method: THROUGHOUT / ESU R: 0.076 / ESU R Free: 0.073 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.21169 2419 5 %RANDOM
Rwork0.19414 ---
obs0.19503 45527 98.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 14.669 Å2
Baniso -1Baniso -2Baniso -3
1-0.05 Å20 Å20 Å2
2--0.34 Å20 Å2
3----0.39 Å2
Refinement stepCycle: LAST / Resolution: 1.45→35.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2203 0 51 204 2458
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0222310
X-RAY DIFFRACTIONr_angle_refined_deg1.1471.9643112
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9385280
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.71124.057106
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.92815394
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.1411515
X-RAY DIFFRACTIONr_chiral_restr0.080.2328
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021745
X-RAY DIFFRACTIONr_nbd_refined0.20.2976
X-RAY DIFFRACTIONr_nbtor_refined0.3030.21578
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.090.2158
X-RAY DIFFRACTIONr_metal_ion_refined0.2610.210
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1750.239
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0680.216
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined0.3680.21
X-RAY DIFFRACTIONr_mcbond_it0.6521.51433
X-RAY DIFFRACTIONr_mcangle_it1.07122239
X-RAY DIFFRACTIONr_scbond_it1.63431003
X-RAY DIFFRACTIONr_scangle_it2.4434.5873
LS refinement shellResolution: 1.45→1.491 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.202 171 -
Rwork0.209 3118 -
obs-4525 93.44 %

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