[English] 日本語
Yorodumi
- PDB-4z0k: Rapid development of two Factor IXa inhibitors from Hit to Lead -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 4z0k
TitleRapid development of two Factor IXa inhibitors from Hit to Lead
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 / 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
Chem-4LN / 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 26, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 20, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

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


Theoretical massNumber of molelcules
Total (without water)33,6156
Polymers32,9472
Non-polymers6684
Water6,215345
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1560 Å2
ΔGint-10 kcal/mol
Surface area13770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.946, 98.946, 94.693
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

-
Components

-
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 residue 227-461)
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: 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

-
Non-polymers , 5 types, 349 molecules

#3: Chemical ChemComp-4LN / N-[(2R)-10-hydroxy-2,7-dimethyl-1,2,3,4-tetrahydropyrido[1,2-b]indazol-2-yl]-4-(4H-1,2,4-triazol-4-yl)benzamide


Mass: 402.449 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22N6O2
#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: Chemical ChemComp-CL / CHLORIDE ION


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


Mass: 18.015 Da / Num. of mol.: 345 / Source method: isolated from a natural source / Formula: H2O

-
Details

Has protein modificationY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 2.78 Å3/Da / Density % sol: 55.7 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: 50 mM Tris, pH 7.2, 1.2 M ammonium sulfate, 2.0 M sodium chloride

-
Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 19, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.407→63.537 Å / Num. obs: 67030 / % possible obs: 99.8 % / Redundancy: 5 % / Biso Wilson estimate: 19.45 Å2 / Rmerge(I) obs: 0.063 / Net I/σ(I): 13.9
Reflection shellResolution: 1.407→1.411 Å / Redundancy: 4.6 % / Rmerge(I) obs: 0.55 / Mean I/σ(I) obs: 2.2 / % possible all: 97.2

-
Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
XDSdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1RFN

1rfn


Resolution: 1.41→20.64 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.967 / 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
Rfree0.165 3368 5.06 %RANDOM
Rwork0.147 ---
obs0.148 66523 99.8 %-
Displacement parametersBiso mean: 25.66 Å2
Baniso -1Baniso -2Baniso -3
1-0.2373 Å20 Å20 Å2
2--0.2373 Å20 Å2
3----0.4746 Å2
Refine analyzeLuzzati coordinate error obs: 0.152 Å
Refinement stepCycle: LAST / Resolution: 1.41→20.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2244 0 45 345 2634
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014588HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.118276HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d996SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes57HARMONIC2
X-RAY DIFFRACTIONt_gen_planes720HARMONIC5
X-RAY DIFFRACTIONt_it4588HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion4.66
X-RAY DIFFRACTIONt_other_torsion12.49
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion301SEMIHARMONIC5
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_contact5282SEMIHARMONIC4
LS refinement shellResolution: 1.41→1.45 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2024 260 5.25 %
Rwork0.1923 4691 -
all0.1928 4951 -
obs--99.81 %
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)
10.9430.15990.04431.2267-0.47921.3124-0.03640.0534-0.1257-0.15960.07610.11430.18590.0186-0.0396-0.0164-0.0009-0.0052-0.08180.0023-0.0545-3.2478-33.4781-3.2556
20.5216-0.18530.25630.6761-0.32551.589-0.0401-0.10270.04430.0561-0.04180.0153-0.16340.19680.0819-0.00860.0034-0.00510.02270.0051-0.0445.4815-28.506120.2883
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more