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- PDB-4zae: Development of a novel class of potent and selective FIXa inhibitors -

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Basic information

Entry
Database: PDB / ID: 4zae
TitleDevelopment of a novel class of potent and selective FIXa inhibitors
Components(Coagulation factor ...) 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 / Laminin / Coagulation Factor Xa inhibitory site / Laminin / 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. ...Peptidase S1A, coagulation factor VII/IX/X/C/Z / Coagulation factor-like, Gla domain superfamily / Laminin / Coagulation Factor Xa inhibitory site / Laminin / 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 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-4M1 / Coagulation factor IX
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.86 Å
AuthorsHruza, A. / Reichert, P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Development of a novel class of potent and selective FIXa inhibitors.
Authors: Zhang, T. / Andre, P. / Bateman, T.J. / Chen, Y.H. / Desai, K. / Ellsworth, K. / Geissler, W.M. / Guo, L. / Hruza, A. / Jian, T. / Meng, D. / Parker, D.L. / Qian, X. / Reichert, P. / Sherer, ...Authors: Zhang, T. / Andre, P. / Bateman, T.J. / Chen, Y.H. / Desai, K. / Ellsworth, K. / Geissler, W.M. / Guo, L. / Hruza, A. / Jian, T. / Meng, D. / Parker, D.L. / Qian, X. / Reichert, P. / Sherer, E.C. / Shu, M. / Smith, C.J. / Sonatore, L.M. / Tschirret-Guth, R. / Nolting, A.F. / Orr, R. / Campeau, L.C. / Araki, K. / Nishimura, T. / Sakurada, I. / Wood, H.B.
History
DepositionApr 13, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 3, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 28, 2015Group: Database references
Revision 1.2Nov 22, 2017Group: Database references / Derived calculations / Refinement description
Category: citation / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _pdbx_struct_oper_list.symmetry_operation / _software.classification
Revision 1.3Sep 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 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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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)33,6825
Polymers32,9472
Non-polymers7363
Water4,684260
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1570 Å2
ΔGint-10 kcal/mol
Surface area13650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.452, 99.452, 94.737
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 / Christmas factor / Plasma thromboplastin component / PTC


Mass: 26104.703 Da / Num. of mol.: 1 / Fragment: Peptidase S1 domain (UNP residues 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 / Christmas factor / Plasma thromboplastin component / PTC


Mass: 6841.809 Da / Num. of mol.: 1 / Fragment: EG-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 , 4 types, 263 molecules

#3: Chemical ChemComp-4M1 / 2,6-dichloro-N-[(2R)-2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-(4H-1,2,4-triazol-4-yl)benzamide


Mass: 505.398 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H22Cl2N6O
#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


Mass: 207.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H17NO3S / Comment: pH buffer*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 260 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.82 Å3/Da / Density % sol: 56.33 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 9
Details: 50 mM CHES, pH 9.0, 1.3 M tri-sodium citrate and 3 mM compound (cross seeded with crystals grown from 50 mM Tris, pH 7.2, 1.45 M ammonium sulfate, 2.0 M sodium chloride and 3 mM compound)

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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: Apr 24, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.857→63.728 Å / Num. obs: 29508 / % possible obs: 100 % / Redundancy: 5.2 % / Biso Wilson estimate: 24.32 Å2 / Rmerge(I) obs: 0.078 / Rsym value: 0.078 / Net I/σ(I): 14.8
Reflection shellResolution: 1.857→1.863 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.575 / Mean I/σ(I) obs: 0.575 / % possible all: 100

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Processing

Software
NameVersionClassification
XDS(VERSION December 29data reduction
SCALAdata scaling
MOLREPphasing
BUSTER2.11.4refinement
Cootmodel building
autoPROCdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1RFN

1rfn


Resolution: 1.86→63.7 Å / Cor.coef. Fo:Fc: 0.9646 / Cor.coef. Fo:Fc free: 0.9546 / SU R Cruickshank DPI: 0.138 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.099 / SU Rfree Blow DPI: 0.094 / SU Rfree Cruickshank DPI: 0.095
RfactorNum. reflection% reflectionSelection details
Rfree0.1741 1475 5.02 %RANDOM
Rwork0.1477 ---
obs0.149 29369 99.98 %-
Displacement parametersBiso mean: 32.41 Å2
Baniso -1Baniso -2Baniso -3
1--1.0361 Å20 Å20 Å2
2---1.0361 Å20 Å2
3---2.0722 Å2
Refine analyzeLuzzati coordinate error obs: 0.193 Å
Refinement stepCycle: LAST / Resolution: 1.86→63.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4453 0 49 260 4762
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014602HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.088304HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d991SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes56HARMONIC2
X-RAY DIFFRACTIONt_gen_planes738HARMONIC5
X-RAY DIFFRACTIONt_it4602HARMONIC20
X-RAY DIFFRACTIONt_nbd4SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion4.26
X-RAY DIFFRACTIONt_other_torsion13.63
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion299SEMIHARMONIC5
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_contact5054SEMIHARMONIC4
LS refinement shellResolution: 1.86→1.93 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.194 155 5.37 %
Rwork0.1865 2729 -
all0.1869 2884 -
obs--99.98 %
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)
11.32720.515-0.37431.5309-0.51582.1672-0.1630.1004-0.1161-0.22530.07640.01070.4164-0.00060.08670.0193-0.00140.0285-0.1265-0.0058-0.1313-3.4237-33.678-3.2478
21.0688-0.0410.47181.5175-0.69831.7873-0.0313-0.11360.07830.1096-0.1052-0.03-0.16260.21360.13650.00570.0041-0.01540.02460.0083-0.06515.8375-28.472419.8828
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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