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- PDB-6x5j: Discovery of Hydroxy Pyrimidine Factor IXa Inhibitors -

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Basic information

Entry
Database: PDB / ID: 6x5j
TitleDiscovery of Hydroxy Pyrimidine Factor IXa Inhibitors
Components(Coagulation factor ...Coagulation) 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 / Coagulation Factor Xa inhibitory site / Laminin / Laminin / EGF-type aspartate/asparagine hydroxylation site / EGF-like domain / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. ...Peptidase S1A, coagulation factor VII/IX/X/C/Z / Coagulation factor-like, Gla domain superfamily / Coagulation Factor Xa inhibitory site / Laminin / Laminin / EGF-type aspartate/asparagine hydroxylation site / EGF-like domain / 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 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-6NH / CITRIC ACID / Coagulation factor IX
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.513 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

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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)34,32710
Polymers33,0332
Non-polymers1,2948
Water2,360131
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4130 Å2
ΔGint-17 kcal/mol
Surface area13250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.548, 100.548, 98.495
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 / Factor IX / Christmas factor / Plasma thromboplastin component / PTC


Mass: 26190.818 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 / 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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-6NH / 2-(4-HYDROXY-5-PHENYL-1H-PYRAZOL-3-YL)-1H-BENZOIMIDAZOLE-5-CARBOXAMIDINE


Mass: 318.333 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H14N6O / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-NA / SODIUM ION


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


Mass: 192.124 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H8O7
#7: Water ChemComp-HOH / water / 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

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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: 3.77 Å3/Da / Density % sol: 67.36 %
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: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Dec 8, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.513→70.361 Å / Num. obs: 17291 / % possible obs: 97.4 % / Redundancy: 4 % / Rmerge(I) obs: 0.058 / Rsym value: 0.058 / Net I/σ(I): 18.6
Reflection shellResolution: 2.513→2.556 Å / Redundancy: 4 % / Rmerge(I) obs: 0.62 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 159 / Rsym value: 0.62 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
Aimlessdata scaling
autoBUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.513→70.36 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.929 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.313 / SU Rfree Blow DPI: 0.22
RfactorNum. reflection% reflectionSelection details
Rfree0.2251 822 -RANDOM
Rwork0.1985 ---
obs0.1998 17285 97.3 %-
Displacement parametersBiso mean: 64.08 Å2
Baniso -1Baniso -2Baniso -3
1--4.8652 Å20 Å20 Å2
2---4.8652 Å20 Å2
3---9.7304 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: LAST / Resolution: 2.513→70.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2214 0 89 131 2434
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0084626HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.018323HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1375SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes793HARMONIC5
X-RAY DIFFRACTIONt_it2384HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion295SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3354SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.56
X-RAY DIFFRACTIONt_other_torsion14.08
LS refinement shellResolution: 2.513→2.53 Å
RfactorNum. reflection% reflection
Rfree0.2821 15 -
Rwork0.2376 --
obs--99.03 %
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)
11.94-0.15441.15812.384-0.09513.2791-0.01960.0635-0.08160.0635-0.0257-0.194-0.0816-0.1940.0453-0.19280.0080.0232-0.08730.0252-0.091331.062611.238718.2264
210.8368-5.0107-0.54526.6314-0.26422.90520.1895-0.5547-0.1712-0.5547-0.09470.7724-0.17120.7724-0.09480.0229-0.09820.10840.32240.18190.197750.535816.47064.126
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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