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- PDB-4cr5: Creating novel F1 inhibitors through fragment based lead generati... -

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Basic information

Entry
Database: PDB / ID: 4cr5
TitleCreating novel F1 inhibitors through fragment based lead generation and structure aided drug design
ComponentsCOAGULATION FACTOR XIA
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 / identical protein binding / membrane / 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 / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family ...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 / 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
6-chloroquinolin-2(1H)-one / Coagulation factor XI
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 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 25, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 11, 2015Provider: repository / Type: Initial release
Revision 2.0Apr 4, 2018Group: Advisory / Atomic model / Data collection
Category: atom_site / diffrn_source / pdbx_unobs_or_zero_occ_atoms
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.label_atom_id / _atom_site.type_symbol / _diffrn_source.type
Revision 2.1Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_entry_details / pdbx_modification_feature / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
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

Downloads & links

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Assembly

Deposited unit
A: COAGULATION FACTOR XIA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,6049
Polymers26,7521
Non-polymers8528
Water3,549197
1
A: COAGULATION FACTOR XIA
hetero molecules

A: COAGULATION FACTOR XIA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,20918
Polymers53,5052
Non-polymers1,70416
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_545x,-y-1,-z1
Buried area3150 Å2
ΔGint-157.5 kcal/mol
Surface area21820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.990, 120.990, 120.990
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-2033-

HOH

21A-2067-

HOH

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Components

#1: Protein COAGULATION FACTOR XIA / 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-0TU / 6-chloroquinolin-2(1H)-one


Mass: 179.603 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H6ClNO
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 197 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.76 Å3/Da / Density % sol: 55.41 % / 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: ROTATING ANODE / Type: RIGAKU FR-E+ / Wavelength: 1.5418
DetectorType: A200-CU / Detector: CCD / Date: Feb 26, 2010 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→24.7 Å / Num. obs: 20045 / % possible obs: 99.9 % / Observed criterion σ(I): 2 / Redundancy: 8.7 % / Rmerge(I) obs: 0.15 / Net I/σ(I): 11
Reflection shellResolution: 2→2.05 Å / Redundancy: 8.1 % / Rmerge(I) obs: 0.62 / Mean I/σ(I) obs: 3.3 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→24.71 Å / Cor.coef. Fo:Fc: 0.915 / Cor.coef. Fo:Fc free: 0.874 / Cross valid method: THROUGHOUT / ESU R: 0.199 / ESU R Free: 0.176 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.24724 974 5.1 %RANDOM
Rwork0.20305 ---
obs0.20522 18080 94.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 15.423 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2→24.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1881 0 47 197 2125
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0191987
X-RAY DIFFRACTIONr_bond_other_d00.021829
X-RAY DIFFRACTIONr_angle_refined_deg1.2151.9542708
X-RAY DIFFRACTIONr_angle_other_deg3.6283.0044201
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2085243
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.07123.93389
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.7415330
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.361512
X-RAY DIFFRACTIONr_chiral_restr0.0710.2292
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022254
X-RAY DIFFRACTIONr_gen_planes_other0.0060.02461
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
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: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.269 78 -
Rwork0.212 1309 -
obs--94.42 %

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