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

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Basic information

Entry
Database: PDB / ID: 4cre
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
6-chloro-4-methyl-1H-quinolin-2-one / Coagulation factor XI
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.73 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
Revision 1.1Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
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)27,72910
Polymers26,7661
Non-polymers9629
Water5,170287
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)83,18630
Polymers80,2993
Non-polymers2,88627
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation9_555y,z,x1
crystal symmetry operation5_555z,x,y1
Buried area6940 Å2
ΔGint-313.1 kcal/mol
Surface area31500 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-2108-

HOH

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Components

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


Mass: 26766.395 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-MVN / 6-chloro-4-methyl-1H-quinolin-2-one


Mass: 193.630 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H8ClNO
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 287 / 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: 2.76 Å3/Da / Density % sol: 55.39 % / 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: RIGAKU SATURN A200 / Detector: CCD / Date: Dec 16, 2009 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.73→23.8 Å / Num. obs: 31069 / % possible obs: 98.7 % / Observed criterion σ(I): 2 / Redundancy: 9.3 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 21.4
Reflection shellResolution: 1.73→1.77 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.56 / Mean I/σ(I) obs: 2.9 / % 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: 1.73→23.8 Å / Cross valid method: THROUGHOUT / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.197 1536 5 %RANDOM
Rwork0.173 ---
obs0.174 28983 98.1 %-
Refinement stepCycle: LAST / Resolution: 1.73→23.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1882 0 53 287 2222

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