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

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Basic information

Entry
Database: PDB / ID: 4crd
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


Intrinsic Pathway of Fibrin Clot Formation / coagulation factor XIa / serine-type aminopeptidase activity / positive regulation of fibrinolysis / plasminogen activation / blood coagulation, intrinsic pathway / heparin binding / blood coagulation / serine-type endopeptidase activity / extracellular space ...Intrinsic Pathway of Fibrin Clot Formation / coagulation factor XIa / serine-type aminopeptidase activity / positive regulation of fibrinolysis / plasminogen activation / blood coagulation, intrinsic pathway / heparin binding / blood coagulation / serine-type endopeptidase activity / extracellular space / extracellular exosome / membrane / extracellular region / identical protein binding / plasma membrane
Serine proteases, trypsin domain / Peptidase S1A, chymotrypsin family / PAN/Apple domain profile. / Serine proteases, trypsin domain profile. / Apple domain. / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin family, histidine active site. / Trypsin / PAN domain / Serine proteases, trypsin family, serine active site ...Serine proteases, trypsin domain / Peptidase S1A, chymotrypsin family / PAN/Apple domain profile. / Serine proteases, trypsin domain profile. / Apple domain. / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin family, histidine active site. / Trypsin / PAN domain / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site / Peptidase S1, PA clan / PAN/Apple domain / Apple domain
Coagulation factor XI
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MAD / Resolution: 2.1 Å
AuthorsSandmark, 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. / Roth, R. / Sandmark, J. / Tigerstrom, A. / Oster, L.
Validation Report
SummaryFull reportAbout validation report
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)27,5585
Polymers26,7521
Non-polymers8064
Water1,36976
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)82,67415
Polymers80,2573
Non-polymers2,41712
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation9_555y,z,x1
crystal symmetry operation5_555z,x,y1
Buried area3890 Å2
ΔGint-132.7 kcal/mol
Surface area31240 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)120.535, 120.535, 120.535
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-1245-

SO4

21A-1245-

SO4

31A-1247-

SO4

41A-1247-

SO4

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Components

#1: Protein/peptide 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-OTJ / Methyl N-[4-[5-chloro-2-[[3-[5-chloro-2-(tetrazol-1-yl)phenyl]propanoylamino]methyl]-1H-imidazol-4-yl]phenyl]carbamate


Mass: 517.368 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22Cl2N8O3
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4 / Sulfate
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / Source method: isolated from a natural source / Formula: H2O / Water

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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: 2.73 Å3/Da / Density % sol: 54.88 % / 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: Jun 25, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.94 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 17077 / % possible obs: 99.5 % / Observed criterion σ(I): 2 / Redundancy: 5.8 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 11.4
Reflection shellResolution: 2.1→2.15 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.51 / Mean I/σ(I) obs: 2.4 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MAD / Resolution: 2.1→85.38 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.945 / Cross valid method: THROUGHOUT / ESU R: 0.208 / ESU R Free: 0.169 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.22032 857 5.1 %RANDOM
Rwork0.19057 ---
Obs0.1922 15814 97.05 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 41.817 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.1→85.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1868 0 50 76 1994
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal targetNumber
r_bond_refined_d0.010.0191976
r_bond_other_d00.021802
r_angle_refined_deg1.3911.9582686
r_angle_other_deg3.64534148
r_dihedral_angle_1_deg6.6345237
r_dihedral_angle_2_deg35.40223.79387
r_dihedral_angle_3_deg13.77315328
r_dihedral_angle_4_deg16.8671512
r_chiral_restr0.0770.2283
r_gen_planes_refined0.0050.022267
r_gen_planes_other0.0060.02456
r_nbd_refined
r_nbd_other
r_nbtor_refined
r_nbtor_other
r_xyhbond_nbd_refined
r_xyhbond_nbd_other
r_metal_ion_refined
r_metal_ion_other
r_symmetry_vdw_refined
r_symmetry_vdw_other
r_symmetry_hbond_refined
r_symmetry_hbond_other
r_symmetry_metal_ion_refined
r_symmetry_metal_ion_other
r_mcbond_it2.3013.92948
r_mcbond_other2.2923.916947
r_mcangle_it3.1455.8681185
r_mcangle_other
r_scbond_it2.9974.3471028
r_scbond_other
r_scangle_it
r_scangle_other
r_long_range_B_refined
r_long_range_B_other
r_rigid_bond_restr
r_sphericity_free
r_sphericity_bonded
LS refinement shellResolution: 2.1→2.155 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.279 63 -
Rwork0.258 1099 -
Obs--91.14 %

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