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- PDB-2uwl: Selective and Dual Action Orally Active Inhibitors of Thrombin an... -

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Basic information

Entry
Database: PDB / ID: 2uwl
TitleSelective and Dual Action Orally Active Inhibitors of Thrombin and Factor Xa
Components(COAGULATION FACTOR X) x 2
KeywordsHYDROLASE / TARGET HOPPING / SERINE PROTEASE / EGF-LIKE DOMAIN / POLYMORPHISM / GLYCOPROTEIN / HYDROXYLATION / CALCIUM / ZYMOGEN / COMPLEX / PROTEASE / BLOOD COAGULATION / GAMMA- CARBOXYGLUTAMIC ACID / CLEAVAGE ON PAIR OF BASIC RESIDUES
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-895 / Coagulation factor X
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.9 Å
AuthorsYoung, R.J. / Brown, D. / Burns-Kurtis, C.L. / Chan, C. / Convery, M.A. / Hubbard, J.A. / Kelly, H.A. / Pateman, A.J. / Patikis, A. / Senger, S. ...Young, R.J. / Brown, D. / Burns-Kurtis, C.L. / Chan, C. / Convery, M.A. / Hubbard, J.A. / Kelly, H.A. / Pateman, A.J. / Patikis, A. / Senger, S. / Shah, G.P. / Toomey, J.R. / Watson, N.S. / Zhou, P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: Selective and Dual Action Orally Active Inhibitors of Thrombin and Factor Xa.
Authors: Young, R.J. / Brown, D. / Burns-Kurtis, C.L. / Chan, C. / Convery, M.A. / Hubbard, J.A. / Kelly, H.A. / Pateman, A.J. / Patikis, A. / Senger, S. / Shah, G.P. / Toomey, J.R. / Watson, N.S. / Zhou, P.
History
DepositionMar 22, 2007Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 24, 2007Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf
Revision 1.4Nov 20, 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 "AA" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AA" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 8-STRANDED BARREL THIS IS REPRESENTED BY A 9-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL. THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 7-STRANDED BARREL THIS IS REPRESENTED BY A 8-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
B: COAGULATION FACTOR X
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,2093
Polymers43,7612
Non-polymers4481
Water3,603200
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)56.547, 72.573, 79.072
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 / ACTIVATED FACTOR XA HEAVY CHAIN / STUART FACTOR / STUART-PROWER FACTOR


Mass: 28550.596 Da / Num. of mol.: 1 / Fragment: ACTIVATED DESGLA, RESIDUES 235-488 / Source method: isolated from a natural source
Details: PURCHASED FROM ENZYME RESEARCH LABS. ISOLATED FROM HUMAN BLOOD
Source: (natural) HOMO SAPIENS (human) / References: UniProt: P00742, coagulation factor Xa
#2: Protein COAGULATION FACTOR X / ACTIVATED FACTOR XA LIGHT CHAIN / STUART FACTOR / STUART-PROWER FACTOR


Mass: 15210.793 Da / Num. of mol.: 1 / Fragment: ACTIVATED DESGLA, RESIDUES 46-179 / Source method: isolated from a natural source
Details: PURCHASED FROM ENZYME RESEARCH LABS. ISOLATED FROM HUMAN BLOOD
Source: (natural) HOMO SAPIENS (human) / References: UniProt: P00742, coagulation factor Xa
#3: Chemical ChemComp-895 / 2-(5-CHLORO-2-THIENYL)-N-{(3S)-1-[(1S)-1-METHYL-2-MORPHOLIN-4-YL-2-OXOETHYL]-2-OXOPYRROLIDIN-3-YL}ETHENESULFONAMIDE


Mass: 447.957 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H22ClN3O5S2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 200 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Sequence detailsSOME RESIDUES IN CHAIN ARE NOT SEEN IN THE ELECTRON DENSITY. SEQUENCE DATABASE RESIDUES 1-45 (THE ...SOME RESIDUES IN CHAIN ARE NOT SEEN IN THE ELECTRON DENSITY. SEQUENCE DATABASE RESIDUES 1-45 (THE GLA DOMAIN) WERE BIOCHEMICALLY REMOVED IN CHAIN B

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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: 2.36 Å3/Da / Density % sol: 33.63 %
Crystal growpH: 5.75
Details: 18% PEG6K, 50MM HEPES PH5.75, 10MM CACL2, 150MM NACL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SRS / Beamline: PX14.1 / Wavelength: 1.488
DetectorType: ADSC CCD / Detector: CCD / Date: May 20, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.488 Å / Relative weight: 1
ReflectionResolution: 1.9→20 Å / Num. obs: 26374 / % possible obs: 99.7 % / Observed criterion σ(I): 0 / Redundancy: 3.97 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 23.9
Reflection shellResolution: 1.9→1.97 Å / Rmerge(I) obs: 0.44 / Mean I/σ(I) obs: 2.8 / % possible all: 99.7

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Processing

Software
NameVersionClassification
REFMAC5.3.0006refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1EZQ

1ezq


Resolution: 1.9→19.96 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.941 / SU B: 3.402 / SU ML: 0.101 / Cross valid method: THROUGHOUT / ESU R: 0.151 / ESU R Free: 0.144 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.238 1330 5.1 %RANDOM
Rwork0.194 ---
obs0.196 24884 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 40.66 Å2
Baniso -1Baniso -2Baniso -3
1-0.53 Å20 Å20 Å2
2---1.47 Å20 Å2
3---0.94 Å2
Refinement stepCycle: LAST / Resolution: 1.9→19.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2226 0 28 200 2454
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0222311
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4681.9583124
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4165284
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.41724.112107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.62815393
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.8821515
X-RAY DIFFRACTIONr_chiral_restr0.1140.2333
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021753
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1990.2999
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3140.21557
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1740.2177
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1750.232
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1790.227
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.18721458
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.45342264
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.954984
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.4556860
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
LS refinement shellResolution: 1.9→1.95 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.321 98
Rwork0.255 1816

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