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- PDB-4yzu: Rapid development of two Factor IXa inhibitors from Hit to Lead -

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Basic information

Entry
Database: PDB / ID: 4yzu
TitleRapid development of two Factor IXa inhibitors from Hit to Lead
Components(Coagulation factor ...Coagulation) x 2
KeywordsHYDROLASE/HYDROLASE INHIBITOR / SERINE PROTEINASE / BLOOD COAGULATION / COAGULATION FACTOR / HYDROLASE-HYDROLASE INHIBITOR complex
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-4K6 / Coagulation factor IX
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.41 Å
AuthorsHruza, A. / Reichert, P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Rapid development of two factor IXa inhibitors from hit to lead.
Authors: Parker, D.L. / Walsh, S. / Li, B. / Kim, E. / Sharipour, A. / Smith, C. / Chen, Y.H. / Berger, R. / Harper, B. / Zhang, T. / Park, M. / Shu, M. / Wu, J. / Xu, J. / Dewnani, S. / Sherer, E.C. ...Authors: Parker, D.L. / Walsh, S. / Li, B. / Kim, E. / Sharipour, A. / Smith, C. / Chen, Y.H. / Berger, R. / Harper, B. / Zhang, T. / Park, M. / Shu, M. / Wu, J. / Xu, J. / Dewnani, S. / Sherer, E.C. / Hruza, A. / Reichert, P. / Geissler, W. / Sonatore, L. / Ellsworth, K. / Balkovec, J. / Greenlee, W. / Wood, H.B.
History
DepositionMar 25, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 20, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Advisory / Database references ...Advisory / Database references / Derived calculations / Refinement description / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_struct_oper_list / pdbx_validate_close_contact / software
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)33,5736
Polymers32,9472
Non-polymers6264
Water6,035335
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1570 Å2
ΔGint-10 kcal/mol
Surface area13940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.911, 98.911, 94.610
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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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: 26104.703 Da / Num. of mol.: 1 / Fragment: Peptidase S1 domain (UNP residue 227-461) / Mutation: R150A
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 / Fragment: EGF-like 2 domain (UNP residues 131-191)
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, 339 molecules

#3: Chemical ChemComp-4K6 / N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)ethyl]-4-(4H-1,2,4-triazol-4-yl)benzamide


Mass: 360.412 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20N6O
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-NHE / 2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID / N-CYCLOHEXYLTAURINE / CHES / CHES (buffer)


Mass: 207.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H17NO3S / Comment: pH buffer*YM
#6: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 335 / Source method: isolated from a natural source / Formula: H2O

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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: 2.75 Å3/Da / Density % sol: 55.31 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 9.5
Details: 0.05 M Tris, pH 7.2, 1.2 M ammonium sulfate, 2.0 M sodium chloride

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 1, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.407→41.41 Å / Num. obs: 66410 / % possible obs: 99.2 % / Redundancy: 5.1 % / Biso Wilson estimate: 20.48 Å2 / Rmerge(I) obs: 0.044 / Net I/σ(I): 18.5
Reflection shellResolution: 1.407→1.412 Å / Redundancy: 5.1 % / Rmerge(I) obs: 0.593 / Mean I/σ(I) obs: 2.5 / % possible all: 97.1

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
MOLREPphasing
XDS(VERSION December 6data reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1RFN

1rfn


Resolution: 1.41→20.64 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.972 / SU R Cruickshank DPI: 0.049 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.045 / SU Rfree Blow DPI: 0.046 / SU Rfree Cruickshank DPI: 0.046
RfactorNum. reflection% reflectionSelection details
Rfree0.161 3271 4.96 %RANDOM
Rwork0.145 ---
obs0.146 65993 99.2 %-
Displacement parametersBiso mean: 26.65 Å2
Baniso -1Baniso -2Baniso -3
1-0.1127 Å20 Å20 Å2
2--0.1127 Å20 Å2
3----0.2254 Å2
Refine analyzeLuzzati coordinate error obs: 0.147 Å
Refinement stepCycle: LAST / Resolution: 1.41→20.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2267 0 42 335 2644
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014692HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.118463HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1023SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes58HARMONIC2
X-RAY DIFFRACTIONt_gen_planes741HARMONIC5
X-RAY DIFFRACTIONt_it4692HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion4.61
X-RAY DIFFRACTIONt_other_torsion13.85
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion309SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5305SEMIHARMONIC4
LS refinement shellResolution: 1.41→1.45 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.1916 252 5.21 %
Rwork0.1862 4585 -
all0.1865 4837 -
obs--99.2 %
Refinement TLS params.

Method: refined / 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)
10.98970.3519-0.0291.2764-0.41991.0777-0.04610.0528-0.1011-0.19410.06150.03680.153-0.0109-0.0154-0.0146-0.00030.0021-0.08370.0034-0.051-3.253-33.5525-3.1384
20.4661-0.34640.2730.6276-0.32881.8557-0.0467-0.11420.04540.0561-0.0525-0.034-0.20470.16160.0991-0.0223-0.01-0.01770.00410.0082-0.01755.2559-28.193120.4195
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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