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- PDB-2xbv: Factor Xa in complex with a pyrrolidine-3,4-dicarboxylic acid inh... -

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Basic information

Entry
Database: PDB / ID: 2xbv
TitleFactor Xa in complex with a pyrrolidine-3,4-dicarboxylic acid inhibitor
Components
  • ACTIVATED FACTOR XA HEAVY CHAIN
  • FACTOR X LIGHT CHAIN
KeywordsBLOOD CLOTTING / COAGULATION FACTOR / HYDROLASE / HYDROXYLATION / 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 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 / Coagulation Factor Xa inhibitory site / Laminin / Laminin / EGF-type aspartate/asparagine hydroxylation site / EGF-like domain / 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 / Coagulation Factor Xa inhibitory site / Laminin / Laminin / EGF-type aspartate/asparagine hydroxylation site / EGF-like domain / 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-XBV / Coagulation factor X
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 1.66 Å
AuthorsBanner, D.W. / Benz, J. / Schlatter, D. / Anselm, L. / Haap, W.
CitationJournal: Bioorg.Med.Chem. / Year: 2010
Title: Discovery of a Factor Xa Inhibitor (3R,4R)-1-(2,2-Difluoro-Ethyl)-Pyrrolidine-3,4-Dicarboxylic Acid 3-[(5-Chloro-Pyridin-2-Yl)-Amide] 4-{[2-Fluoro-4-(2-Oxo-2H-Pyridin-1-Yl)-Phenyl]-Amide} as a Clinical Candidate.
Authors: Anselm, L. / Banner, D.W. / Benz, J. / Groebke Zbinden, K. / Himber, J. / Hilpert, H. / Huber, W. / Kuhn, B. / Mary, J.L. / Otteneder, M.B. / Panday, N. / Ricklin, F. / Stahl, M. / Thomi, S. / Haap, W.
History
DepositionApr 15, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 4, 2010Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
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 7-STRANDED BARREL THIS IS REPRESENTED BY A 8-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 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: ACTIVATED FACTOR XA HEAVY CHAIN
L: FACTOR X LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8175
Polymers33,2342
Non-polymers5833
Water5,134285
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1980 Å2
ΔGint-34.1 kcal/mol
Surface area12800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.940, 105.940, 50.180
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-2034-

HOH

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Components

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Protein , 2 types, 2 molecules AL

#1: Protein ACTIVATED FACTOR XA HEAVY CHAIN


Mass: 27172.980 Da / Num. of mol.: 1 / Fragment: HEAVY CHAIN, RESIDUES 235-475 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P00742, coagulation factor Xa
#2: Protein FACTOR X LIGHT CHAIN /


Mass: 6060.816 Da / Num. of mol.: 1 / Fragment: LIGHTCHAIN, RESIDUES 126-180
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P00742, coagulation factor Xa

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Non-polymers , 4 types, 288 molecules

#3: Chemical ChemComp-XBV / (3R,4R)-1-(2,2-DIFLUORO-ETHYL)-PYRROLIDINE-3,4-DICARBOXYLIC ACID 3-[(5-CHLORO-PYRIDIN-2-YL)-AMIDE]-4-{[2-FLUORO-4-(2-OXO-2H-PYRIDIN-1-YL)-PHENYL]-AMIDE}


Mass: 519.903 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H21ClF3N5O3
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 285 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsENGINEERED RESIDUE IN CHAIN A, ARG 372 TO GLU

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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: 2.25 Å3/Da / Density % sol: 45.5 % / Description: SOLVED FROM EARLIER IN HOUSE STRUCTURES
Crystal growpH: 6.5 / Details: PH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9995
DetectorType: MARRESEARCH / Detector: CCD / Date: Nov 4, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9995 Å / Relative weight: 1
ReflectionResolution: 1.66→20 Å / Num. obs: 34052 / % possible obs: 99.3 % / Observed criterion σ(I): -3 / Redundancy: 8.6 % / Biso Wilson estimate: 26.12 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 19.62
Reflection shellResolution: 1.66→1.76 Å / Redundancy: 7.54 % / Rmerge(I) obs: 0.49 / Mean I/σ(I) obs: 4.26 / % possible all: 97.3

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Processing

Software
NameVersionClassification
BUSTER-TNT2.9.3refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.66→19.52 Å / Cor.coef. Fo:Fc: 0.9542 / Cor.coef. Fo:Fc free: 0.9441 / SU R Cruickshank DPI: 0.102 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.11 / SU Rfree Blow DPI: 0.105 / SU Rfree Cruickshank DPI: 0.1
RfactorNum. reflection% reflectionSelection details
Rfree0.2244 1722 5.1 %RANDOM
Rwork0.192 ---
obs0.1936 34051 99.38 %-
Displacement parametersBiso mean: 31.52 Å2
Baniso -1Baniso -2Baniso -3
1--0.473 Å20 Å20 Å2
2---0.473 Å20 Å2
3---0.946 Å2
Refine analyzeLuzzati coordinate error obs: 0.193 Å
Refinement stepCycle: LAST / Resolution: 1.66→19.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2160 0 38 285 2483
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0122248HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.153037HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d770SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes58HARMONIC2
X-RAY DIFFRACTIONt_gen_planes326HARMONIC5
X-RAY DIFFRACTIONt_it2209HARMONIC20
X-RAY DIFFRACTIONt_nbd11SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion4.17
X-RAY DIFFRACTIONt_other_torsion15.01
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion289SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2763SEMIHARMONIC4
LS refinement shellResolution: 1.66→1.71 Å / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.2507 147 5.32 %
Rwork0.2222 2616 -
all0.2237 2763 -
obs--99.38 %

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