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- PDB-1ql8: FACTOR XA SPECIFIC INHIBITOR IN COMPLEX WITH BOVINE TRYPSIN -

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Basic information

Entry
Database: PDB / ID: 1ql8
TitleFACTOR XA SPECIFIC INHIBITOR IN COMPLEX WITH BOVINE TRYPSIN
ComponentsTRYPSIN
KeywordsSERINE PROTEASE / HYDROLASE / SERINE PROTEINASE
Function / homology
Function and homology information


trypsin / serpin family protein binding / serine protease inhibitor complex / digestion / endopeptidase activity / serine-type endopeptidase activity / proteolysis / extracellular space / metal ion binding
Similarity search - Function
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 ...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-ZEN / Serine protease 1
Similarity search - Component
Biological speciesBOS TAURUS (cattle)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 3 Å
AuthorsStubbs, M.T.
Citation
Journal: Chembiochem / Year: 2002
Title: Ph-Dependent Binding Modes Observed in Trypsin Crystals: Lessons for the Structure-Based Drug Design
Authors: Stubbs, M.T. / Reyda, S. / Dullweber, F. / Moeller, M. / Klebe, G. / Dorsch, D. / Mederski, W.W.K.R. / Wurziger, H.
#1: Journal: J.Med.Chem. / Year: 1998
Title: Structural and Functional Analyses of Benzamidine-Based Inhibitors in Complex with Trypsin: Implications for the Inhibition of Factor Xa, Tpa, and Urokinase
Authors: Renatus, M. / Bode, W. / Huber, R. / Stuerzebecher, J. / Stubbs, M.T.
#2: Journal: Curr.Pharm.Des. / Year: 1996
Title: Structural Aspects of Factor Xa Inhibition
Authors: Stubbs, M.T.
#3: Journal: FEBS Lett. / Year: 1995
Title: Crystal Structures of Factor Xa Specific Inhibitors in Complex with Trypsin: Structural Grounds for Inhibition of Factor Xa and Selectivity Against Thrombin
Authors: Stubbs, M.T. / Huber, R. / Bode, W.
History
DepositionAug 24, 1999Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 25, 2000Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jul 5, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: TRYPSIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,9594
Polymers23,3241
Non-polymers6353
Water61334
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)125.810, 125.810, 125.810
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number199
Space group name H-MI213

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Components

#1: Protein TRYPSIN / / TRYPSINOGEN / BETA-TRYPSIN


Mass: 23324.287 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) BOS TAURUS (cattle) / Organ: PANCREAS / References: UniProt: P00760, trypsin
#2: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-ZEN / [4-(6-CHLORO-NAPHTHALENE-2-SULFONYL)-PIPERAZIN-1-YL]- (3,4,5,6-TETRAHYDRO-2H-[1,4']BIPYRIDINYL-4-YL)- METHANONE


Mass: 499.025 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27ClN4O3S
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 34 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHE 223 AMINO ACIDS OF BOVINE TRYPSIN ARE IDENTIFIED BY THE RESIDUE NUMBERS OF THE HOMOLOGOUS ...THE 223 AMINO ACIDS OF BOVINE TRYPSIN ARE IDENTIFIED BY THE RESIDUE NUMBERS OF THE HOMOLOGOUS CHYMOTRYPSINOGEN. THESE COORDINATES ARE FOR THE CUBIC CRYSTAL FORM OF THE ZENECA:BOVINE TRYPSIN COMPLEX AT PH7. THE CRYSTALS DIFFRACT ONLY TO ABOUT 3A RESOLUTION; THE RESULTING STRUCTURE SHOWS THAT THE PYRIDINE MOIETY ENTERS THE S1 POCKET, BUT DOES NOT PENETRATE IT DEEPLY. NO IONIC INTERACTION IS OBSERVED BETWEEN THE PYRIDINE MOIETY AND ASP189; INSTEAD, THE FORMER HYDROGEN BONDS WITH THE HYDROXYL FUNCTION OF SER190. PRESUMABLY, THERE ARE FURTHER SOLVENT MOLECULES BURIED IN THE POCKET; THERE IS HOWEVER NO DENSITY THAT CAN BE INTERPRETED RELIABLY FOR THEM. DENSITY FOR THE INHIBITOR PETERS OUT FOR THE SECOND PIPERIDINYL RING AND THE CHLORINATED NAPHTHALENE MOIETY; RESIDUAL DENSITY SUGGESTS THAT THESE PARTS ARE AS MODELLED. THE SAME INHIBITOR HAS ALSO BEEN CRYSTALLIZED (A) WITH BOVINE TRYPSIN AT PH 8 (SEE PDB FILE 1QL7), AND (B) WITH RAT TRYPSIN MUTANT X99RT (SEE PDB FILE 1QL9). IN EACH CASE, THE INHIBITOR BINDS IN THE REVERSE DIRECTION TO THAT SEEN HERE. THIS CORRELATES WITH THE MEASURED PKA OF 7.4 FOR THE PYRIDINYL FUNCTION. THE KI AGAINST BOVINE TRYPSIN IS ~50UM AT PH5, AND ~10-20UM AT PH 7.8.

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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: 3.56 Å3/Da / Density % sol: 65.42 %
Crystal growpH: 7
Details: 0.1M IMIDAZOLE PH7.0, 0.3M AMMONIUM SULPHATE, 30% PEG8K, pH 7.00
Crystal grow
*PLUS
Method: vapor diffusion / pH: 7
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
110 mg/mlprotein1drop
22 mg/mlinhibitor1drop
30.1 Mimidazole1reservoirpH7
40.3 Mammonium sulfate1reservoir
530 %PEG80001reservoir

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Data collection

DiffractionMean temperature: 287 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: R-AXIS IV / Detector: IMAGE PLATE / Date: Jul 15, 1998 / Details: MIRRORS
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.9→100 Å / Num. obs: 7494 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 3.6 % / Rmerge(I) obs: 0.147 / Rsym value: 0.147 / Net I/σ(I): 6.4
Reflection shellResolution: 2.9→3 Å / Rmerge(I) obs: 0.543 / Rsym value: 0.543 / % possible all: 99.6

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Processing

Software
NameVersionClassification
X-PLOR3.1refinement
DENZOdata reduction
SCALEPACKdata scaling
X-PLOR3.1phasing
RefinementMethod to determine structure: OTHER / Resolution: 3→10 Å / Data cutoff high absF: 10000000 / Data cutoff low absF: 0.001 / σ(F): 0
RfactorNum. reflection% reflection
Rwork0.19 --
obs0.19 6579 99.9 %
Refine analyzeLuzzati d res low obs: 10 Å
Refinement stepCycle: LAST / Resolution: 3→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1629 0 40 34 1703
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.007
X-RAY DIFFRACTIONx_bond_d_na
X-RAY DIFFRACTIONx_bond_d_prot
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_angle_d_na
X-RAY DIFFRACTIONx_angle_d_prot
X-RAY DIFFRACTIONx_angle_deg1.61
X-RAY DIFFRACTIONx_angle_deg_na
X-RAY DIFFRACTIONx_angle_deg_prot
X-RAY DIFFRACTIONx_dihedral_angle_d24.9
X-RAY DIFFRACTIONx_dihedral_angle_d_na
X-RAY DIFFRACTIONx_dihedral_angle_d_prot
X-RAY DIFFRACTIONx_improper_angle_d1.25
X-RAY DIFFRACTIONx_improper_angle_d_na
X-RAY DIFFRACTIONx_improper_angle_d_prot
X-RAY DIFFRACTIONx_mcbond_it
X-RAY DIFFRACTIONx_mcangle_it
X-RAY DIFFRACTIONx_scbond_it
X-RAY DIFFRACTIONx_scangle_it
LS refinement shellResolution: 3→3.05 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rwork0.27 324 -
obs--99.9 %
Xplor fileSerial no: 1 / Param file: PARHCSDX.PRO / Topol file: TOPHCSDX.PRO
Software
*PLUS
Name: X-PLOR / Version: 3.1 / Classification: refinement
Refinement
*PLUS
Rfactor obs: 0.19 / Rfactor Rwork: 0.19
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_deg24.9
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg1.25
LS refinement shell
*PLUS
Rfactor Rwork: 0.27

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