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- PDB-6x5l: Discovery of Hydroxy Pyrimidine Factor IXa Inhibitors -

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Basic information

Entry
Database: PDB / ID: 6x5l
TitleDiscovery of Hydroxy Pyrimidine Factor IXa Inhibitors
Components(Coagulation factor ...) x 2
KeywordsBLOOD CLOTTING / SERINE PROTEASE / ZYMOGEN / HYDROLASE / GLYCOPROTEIN / HYDROXYLATION / PHOSPHOPROTEIN / SULFATION / HEMOSTASIS / HEMOPHILIA / XASE-LIKE VARIANT / COMMUNICATION CHANNEL / GAMMA-CARBOXYGLUTAMIC ACID / EGF-LIKE DOMAIN / DISEASE MUTATION
Function / homology
Function and homology information


Defective F9 secretion / Defective gamma-carboxylation of F9 / coagulation factor IXa / Defective F9 activation / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / zymogen activation / Extrinsic Pathway of Fibrin Clot Formation / Protein hydroxylation ...Defective F9 secretion / Defective gamma-carboxylation of F9 / coagulation factor IXa / Defective F9 activation / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / zymogen activation / Extrinsic Pathway of Fibrin Clot Formation / Protein hydroxylation / Gamma-carboxylation of protein precursors / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Removal of aminoterminal propeptides from gamma-carboxylated proteins / Intrinsic Pathway of Fibrin Clot Formation / Golgi lumen / blood coagulation / collagen-containing extracellular matrix / endopeptidase activity / endoplasmic reticulum lumen / serine-type endopeptidase activity / calcium ion binding / proteolysis / extracellular space / extracellular exosome / extracellular region / metal ion binding / plasma membrane
Similarity search - Function
Peptidase S1A, coagulation factor VII/IX/X/C/Z / : / Coagulation factor-like, Gla domain superfamily / Laminin / Laminin / Coagulation Factor Xa inhibitory site / EGF-like domain / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. ...Peptidase S1A, coagulation factor VII/IX/X/C/Z / : / Coagulation factor-like, Gla domain superfamily / Laminin / Laminin / Coagulation Factor Xa inhibitory site / EGF-like domain / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain superfamily / Vitamin K-dependent carboxylation domain. / Gla domain profile. / Domain containing Gla (gamma-carboxyglutamate) residues. / Epidermal growth factor-like domain. / EGF-like domain profile. / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain / Ribbon / 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 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
CITRIC ACID / Chem-UQG / Coagulation factor IX
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.246 Å
AuthorsJayne, C.L. / Andreani, T. / Chan, T. / Chelliah, M.V. / Clasby, M.C. / Dwyer, M. / Eagen, K.A. / Fried, S. / Greenlee, W.J. / Guo, Z. ...Jayne, C.L. / Andreani, T. / Chan, T. / Chelliah, M.V. / Clasby, M.C. / Dwyer, M. / Eagen, K.A. / Fried, S. / Greenlee, W.J. / Guo, Z. / Hawes, B. / Hruza, A. / Ingram, R. / Keertikar, K.M. / Neelamkavil, S. / Reichert, P. / Xia, Y. / Chackalamannil, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Discovery of hydroxy pyrimidine Factor IXa inhibitors.
Authors: Jayne, C.L. / Andreani, T. / Chan, T.Y. / Chelliah, M.V. / Clasby, M.C. / Dwyer, M. / Eagen, K.A. / Fried, S. / Greenlee, W.J. / Guo, Z. / Hawes, B. / Hruza, A. / Ingram, R. / Keertikar, K.M. ...Authors: Jayne, C.L. / Andreani, T. / Chan, T.Y. / Chelliah, M.V. / Clasby, M.C. / Dwyer, M. / Eagen, K.A. / Fried, S. / Greenlee, W.J. / Guo, Z. / Hawes, B. / Hruza, A. / Ingram, R. / Keertikar, K.M. / Neelamkavil, S. / Reichert, P. / Xia, Y. / Chackalamannil, S.
History
DepositionMay 26, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 24, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Coagulation factor IX
B: Coagulation factor IX
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,22710
Polymers32,9322
Non-polymers1,2958
Water2,360131
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2750 Å2
ΔGint-20 kcal/mol
Surface area13270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.56, 100.56, 98.202
Angle α, β, γ (deg.)90, 90, 90
Int Tables number96
Space group name H-MP43212

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Components

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Coagulation factor ... , 2 types, 2 molecules AB

#1: Protein Coagulation factor IX / Christmas factor / Plasma thromboplastin component / PTC


Mass: 26089.715 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F9 / Production host: Escherichia coli (E. coli) / References: UniProt: P00740, coagulation factor IXa
#2: Protein Coagulation factor IX / Christmas factor / Plasma thromboplastin component / PTC


Mass: 6841.809 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F9 / Production host: Escherichia coli (E. coli) / References: UniProt: P00740, coagulation factor IXa

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Non-polymers , 5 types, 139 molecules

#3: Chemical ChemComp-UQG / 4-{[5-hydroxy-6-(4-methylphenyl)pyrimidin-4-yl]amino}benzene-1-carboximidamide


Mass: 319.360 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17N5O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Chemical
ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H8O7
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 131 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 3.94 Å3/Da / Density % sol: 68.78 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.6 / Details: 0.1M CITRIC ACID, 20% PEG 6000 / PH range: 5.2 - 6.0

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Data collection

DiffractionMean temperature: 90 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 11, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.25→30 Å / Num. obs: 24249 / % possible obs: 98.2 % / Redundancy: 6.7 % / Rmerge(I) obs: 0.057 / Rsym value: 0.057 / Net I/σ(I): 27.263
Reflection shellResolution: 2.25→2.29 Å / Redundancy: 7.6 % / Rmerge(I) obs: 0.484 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 884 / Rsym value: 0.484 / % possible all: 73.3

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
HKL-2000v1.98.6data reduction
HKL-2000v1.98.6data scaling
autoBUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.246→29.73 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.935 / SU R Cruickshank DPI: 0.308 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.199 / SU Rfree Blow DPI: 0.17 / SU Rfree Cruickshank DPI: 0.167
RfactorNum. reflection% reflectionSelection details
Rfree0.2332 1154 -RANDOM
Rwork0.2047 ---
obs0.2061 24156 98.2 %-
Displacement parametersBiso mean: 58.86 Å2
Baniso -1Baniso -2Baniso -3
1--3.0276 Å20 Å20 Å2
2---3.0276 Å20 Å2
3---6.0552 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: LAST / Resolution: 2.246→29.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2199 0 89 131 2419
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0084593HARMONIC2
X-RAY DIFFRACTIONt_angle_deg18268HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1361SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes780HARMONIC5
X-RAY DIFFRACTIONt_it2364HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion292SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3432SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.83
X-RAY DIFFRACTIONt_other_torsion13.82
LS refinement shellResolution: 2.25→2.27 Å
RfactorNum. reflection% reflection
Rfree0.2985 25 -
Rwork0.2943 --
obs0.2945 484 68.64 %
Refinement TLS params.

Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.6941-0.06910.93072.2057-0.01922.9039-0.02890.0387-0.10260.0387-0.0404-0.192-0.1026-0.1920.0693-0.14830.01830.0171-0.0460.0314-0.109531.098311.366118.2355
211.0766-4.52030.21066.5002-0.29413.87230.2451-0.7072-0.1892-0.7072-0.19150.7525-0.18920.7525-0.05360.0383-0.11270.12470.35170.18430.159550.343316.65354.0408
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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