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- PDB-4crg: Creating novel F1 inhibitors through fragment based lead generati... -

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Basic information

Entry
Database: PDB / ID: 4crg
TitleCreating novel F1 inhibitors through fragment based lead generation and structure aided drug design
ComponentsCOAGULATION FACTOR XIFactor XI
KeywordsHYDROLASE
Function / homology
Function and homology information


coagulation factor XIa / serine-type aminopeptidase activity / Defective F9 activation / positive regulation of fibrinolysis / plasminogen activation / Intrinsic Pathway of Fibrin Clot Formation / blood coagulation / heparin binding / serine-type endopeptidase activity / extracellular space ...coagulation factor XIa / serine-type aminopeptidase activity / Defective F9 activation / positive regulation of fibrinolysis / plasminogen activation / Intrinsic Pathway of Fibrin Clot Formation / blood coagulation / heparin binding / serine-type endopeptidase activity / extracellular space / extracellular exosome / extracellular region / membrane / identical protein binding / plasma membrane
Similarity search - Function
Apple domain. / Apple domain / APPLE domain / PAN/Apple domain profile. / PAN domain / PAN/Apple domain / 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. ...Apple domain. / Apple domain / APPLE domain / PAN/Apple domain profile. / PAN domain / PAN/Apple domain / 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-J4X / Coagulation factor XI
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.25 Å
AuthorsSandmark, J. / Oster, L. / Fjellstrom, O. / Akkaya, S. / Beisel, H.G. / Eriksson, P.O. / Erixon, K. / Gustafsson, D. / Jurva, U. / Kang, D. ...Sandmark, J. / Oster, L. / Fjellstrom, O. / Akkaya, S. / Beisel, H.G. / Eriksson, P.O. / Erixon, K. / Gustafsson, D. / Jurva, U. / Kang, D. / Karis, D. / Knecht, W. / Nerme, V. / Nilsson, I. / Olsson, T. / Redzic, A. / Roth, R. / Tigerstrom, A.
CitationJournal: Plos One / Year: 2015
Title: Creating Novel Activated Factor Xi Inhibitors Through Fragment Based Lead Generation and Structure Aided Drug Design.
Authors: Fjellstrom, O. / Akkaya, S. / Beisel, H. / Eriksson, P. / Erixon, K. / Gustafsson, D. / Jurva, U. / Kang, D. / Karis, D. / Knecht, W. / Nerme, V. / Nilsson, I. / Olsson, T. / Redzic, A. / ...Authors: Fjellstrom, O. / Akkaya, S. / Beisel, H. / Eriksson, P. / Erixon, K. / Gustafsson, D. / Jurva, U. / Kang, D. / Karis, D. / Knecht, W. / Nerme, V. / Nilsson, I. / Olsson, T. / Redzic, A. / Roth, R. / Sandmark, J. / Tigerstrom, A. / Oster, L.
History
DepositionFeb 26, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 11, 2015Provider: repository / Type: Initial release
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP 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

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Assembly

Deposited unit
A: COAGULATION FACTOR XI
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,88710
Polymers26,7521
Non-polymers1,1359
Water5,999333
1
A: COAGULATION FACTOR XI
hetero molecules

A: COAGULATION FACTOR XI
hetero molecules

A: COAGULATION FACTOR XI
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,66230
Polymers80,2573
Non-polymers3,40527
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation9_555y,z,x1
crystal symmetry operation5_555z,x,y1
Buried area7510 Å2
ΔGint-183.6 kcal/mol
Surface area30840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.874, 120.874, 120.874
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number197
Space group name H-MI23
Components on special symmetry positions
IDModelComponents
11A-1496-

SO4

21A-1496-

SO4

31A-2094-

HOH

41A-2209-

HOH

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Components

#1: Protein COAGULATION FACTOR XI / Factor XI / FXI / PLASMA THROMBOPLASTIN ANTECEDENT / PTA / COAGULATION FACTOR XIA LIGHT CHAIN


Mass: 26752.369 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, RESIDUES 388-625 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: PICHIA PASTORIS (fungus) / References: UniProt: P03951, coagulation factor XIa
#2: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-J4X / 6-carbamimidoyl-N-phenyl-4-(pyrimidin-2-ylamino)naphthalene-2-carboxamide


Mass: 382.418 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H18N6O
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 333 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsMUTANT, S75A K78A T97A C123S

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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: 2.75 Å3/Da / Density % sol: 55.28 % / Description: NONE
Crystal growpH: 8.5
Details: 2M AMMONIUM SULFATE, 0.1M TRIS-CL PH 8.5, 0.2M NACL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.94
DetectorType: ADSC CCD / Detector: CCD / Date: Feb 15, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.94 Å / Relative weight: 1
ReflectionResolution: 1.25→49.3 Å / Num. obs: 75396 / % possible obs: 92.8 % / Observed criterion σ(I): 2 / Redundancy: 5.2 % / Biso Wilson estimate: 13.6 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 14.8
Reflection shellResolution: 1.25→1.33 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.74 / Mean I/σ(I) obs: 1.8 / % possible all: 75

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.25→49.35 Å / Cor.coef. Fo:Fc: 0.9336 / Cor.coef. Fo:Fc free: 0.9247 / SU R Cruickshank DPI: 0.043 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.045 / SU Rfree Blow DPI: 0.047 / SU Rfree Cruickshank DPI: 0.045
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY. THE LIGAND J4X IS PLACED IN THE DENSITY IN TWO DIFFERENT ORIENTATIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1951 3777 5.03 %RANDOM
Rwork0.1755 ---
obs0.1764 75043 92.88 %-
Displacement parametersBiso mean: 21.11 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 1.25→49.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1850 0 73 333 2256
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012158HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.112951HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d787SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes51HARMONIC2
X-RAY DIFFRACTIONt_gen_planes355HARMONIC5
X-RAY DIFFRACTIONt_it2158HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion4.63
X-RAY DIFFRACTIONt_other_torsion15.58
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion270SEMIHARMONIC5
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_contact2680SEMIHARMONIC4
LS refinement shellResolution: 1.25→1.28 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2884 229 5.44 %
Rwork0.284 3982 -
all0.2843 4211 -
obs--92.88 %
Refinement TLS params.Method: refined / Origin x: -28.5217 Å / Origin y: -42.8729 Å / Origin z: -10.8567 Å
111213212223313233
T0.0404 Å20.0152 Å20.0067 Å2-0.0037 Å2-0.0034 Å2--0.0263 Å2
L0.7628 °2-0.1013 °2-0.3462 °2-0.5007 °20.0872 °2--0.7934 °2
S0.0266 Å °-0.0076 Å °0.0549 Å °-0.0185 Å °0.0179 Å °-0.0373 Å °-0.0365 Å °0.0276 Å °-0.0445 Å °
Refinement TLS groupSelection details: { A|370 - A|607 }

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