[English] 日本語
Yorodumi
- PDB-5v9t: Crystal structure of selective pyrrolidine amide KDM5a inhibitor ... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 5v9t
TitleCrystal structure of selective pyrrolidine amide KDM5a inhibitor N-{(3R)-1-[3-(propan-2-yl)-1H-pyrazole-5-carbonyl]pyrrolidin-3-yl}cyclopropanecarboxamide (compound 48)
Components(Lysine-specific demethylase ...) x 2
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / histone demethylase / KDM5 / KDM5a / epigenetics / cancer / selective / inhibitor / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


[histone H3]-trimethyl-L-lysine4 demethylase / facultative heterochromatin formation / histone H3K4me/H3K4me2/H3K4me3 demethylase activity / enzyme inhibitor activity / regulation of DNA-binding transcription factor activity / histone demethylase activity / methylated histone binding / Chromatin modifications during the maternal to zygotic transition (MZT) / circadian regulation of gene expression / HDMs demethylate histones ...[histone H3]-trimethyl-L-lysine4 demethylase / facultative heterochromatin formation / histone H3K4me/H3K4me2/H3K4me3 demethylase activity / enzyme inhibitor activity / regulation of DNA-binding transcription factor activity / histone demethylase activity / methylated histone binding / Chromatin modifications during the maternal to zygotic transition (MZT) / circadian regulation of gene expression / HDMs demethylate histones / chromatin DNA binding / histone binding / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / chromatin / nucleolus / regulation of DNA-templated transcription / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
: / : / : / : / : / Lysine-specific demethylase 5, C-terminal helical domain / Lysine-specific demethylase-like domain / PLU-1-like protein / Zinc finger, C5HC2-type / C5HC2 zinc finger ...: / : / : / : / : / Lysine-specific demethylase 5, C-terminal helical domain / Lysine-specific demethylase-like domain / PLU-1-like protein / Zinc finger, C5HC2-type / C5HC2 zinc finger / ARID/BRIGHT DNA binding domain / ARID DNA-binding domain / ARID DNA-binding domain superfamily / ARID/BRIGHT DNA binding domain / ARID domain profile. / BRIGHT, ARID (A/T-rich interaction domain) domain / JmjN domain / jmjN domain / JmjN domain profile. / Small domain found in the jumonji family of transcription factors / JmjC domain, hydroxylase / A domain family that is part of the cupin metalloenzyme superfamily. / JmjC domain / JmjC domain profile. / Zinc finger, PHD-type, conserved site / PHD-finger / Zinc finger PHD-type signature. / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Zinc finger, PHD-type / PHD zinc finger / Zinc finger, FYVE/PHD-type / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Chem-90V / NICKEL (II) ION / Lysine-specific demethylase 5A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.05 Å
AuthorsKiefer, J.R. / Liang, J. / Vinogradova, M.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors.
Authors: Liang, J. / Labadie, S. / Zhang, B. / Ortwine, D.F. / Patel, S. / Vinogradova, M. / Kiefer, J.R. / Mauer, T. / Gehling, V.S. / Harmange, J.C. / Cummings, R. / Lai, T. / Liao, J. / Zheng, X. ...Authors: Liang, J. / Labadie, S. / Zhang, B. / Ortwine, D.F. / Patel, S. / Vinogradova, M. / Kiefer, J.R. / Mauer, T. / Gehling, V.S. / Harmange, J.C. / Cummings, R. / Lai, T. / Liao, J. / Zheng, X. / Liu, Y. / Gustafson, A. / Van der Porten, E. / Mao, W. / Liederer, B.M. / Deshmukh, G. / An, L. / Ran, Y. / Classon, M. / Trojer, P. / Dragovich, P.S. / Murray, L.
History
DepositionMar 23, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 10, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Lysine-specific demethylase 5A
B: Lysine-specific demethylase 5A
G: Lysine-specific demethylase 5A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)183,23711
Polymers182,2773
Non-polymers9608
Water25214
1
A: Lysine-specific demethylase 5A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,1845
Polymers90,7041
Non-polymers4804
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area100 Å2
ΔGint-39 kcal/mol
Surface area27750 Å2
MethodPISA
2
B: Lysine-specific demethylase 5A
G: Lysine-specific demethylase 5A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,0536
Polymers91,5732
Non-polymers4804
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area630 Å2
ΔGint-42 kcal/mol
Surface area29280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)159.615, 159.615, 92.071
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number144
Space group name H-MP31

-
Components

-
Lysine-specific demethylase ... , 2 types, 3 molecules ABG

#1: Protein Lysine-specific demethylase 5A / Histone demethylase JARID1A / Jumonji/ARID domain-containing protein 1A / Retinoblastoma-binding ...Histone demethylase JARID1A / Jumonji/ARID domain-containing protein 1A / Retinoblastoma-binding protein 2 / RBBP-2 / KDM5A


Mass: 90703.938 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM5A, JARID1A, RBBP2, RBP2 / Plasmid: pACGP67 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
References: UniProt: P29375, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With 2-oxoglutarate as one donor, and incorporation of one atom of oxygen into each donor
#2: Protein/peptide Lysine-specific demethylase 5A / Histone demethylase JARID1A / Jumonji/ARID domain-containing protein 1A / Retinoblastoma-binding ...Histone demethylase JARID1A / Jumonji/ARID domain-containing protein 1A / Retinoblastoma-binding protein 2 / RBBP-2 / KDM5A


Mass: 869.063 Da / Num. of mol.: 1 / Fragment: Internal region with unknown reference frame
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM5A, JARID1A, RBBP2, RBP2 / Plasmid: pACGP67 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9

-
Non-polymers , 4 types, 22 molecules

#3: Chemical ChemComp-NI / NICKEL (II) ION / Nickel


Mass: 58.693 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ni
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-90V / N-{(3R)-1-[3-(propan-2-yl)-1H-pyrazole-5-carbonyl]pyrrolidin-3-yl}cyclopropanecarboxamide


Mass: 290.361 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H22N4O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O

-
Experimental details

-
Experiment

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

-
Sample preparation

CrystalDensity Matthews: 3.72 Å3/Da / Density % sol: 66.91 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 7.3
Details: 200 uM inhibitor, 20% PEG3350, 0.1 M HEPES, pH 7.3, 12% glycerol

-
Data collection

DiffractionMean temperature: 193 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1.00001 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 1, 2014
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 3.05→35 Å / Num. obs: 46843 / % possible obs: 92.7 % / Redundancy: 3.1 % / Biso Wilson estimate: 74.96 Å2 / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.046 / Rrim(I) all: 0.089 / Χ2: 2.137 / Net I/σ(I): 16.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
3.05-3.12.40.4970.5230.3530.6131.30893.2
3.1-3.162.60.4590.5590.3230.5651.35994.6
3.16-3.222.60.4420.5990.3080.5421.33394.7
3.22-3.292.60.3890.7120.2680.4761.54694.9
3.29-3.362.60.3290.8050.2270.4021.59894.3
3.36-3.432.50.2990.8350.2060.3651.60993.1
3.43-3.522.40.2440.9110.1710.31.88288.4
3.52-3.622.20.2170.9110.1520.2672.12179.4
3.62-3.723.60.140.9360.0840.1642.90199.1
3.72-3.842.90.1590.9580.1010.1892.43589.9
3.84-3.982.90.1380.9720.0890.1652.35689.2
3.98-4.142.70.0980.9810.0640.1182.34983.3
4.14-4.333.10.0850.990.0520.12.33990.9
4.33-4.553.30.0760.9920.0460.0892.55792.1
4.55-4.843.30.0670.9920.040.0782.43591.4
4.84-5.213.40.0660.9940.0390.0772.36593.4
5.21-5.733.60.0620.9940.0360.0722.25996.9
5.73-6.563.60.0580.9950.0330.0672.20298
6.56-8.244.10.050.9970.0270.0572.33299.1
8.24-354.30.0370.9980.0190.0422.03499.1

-
Processing

Software
NameVersionClassification
SCALEPACKdata scaling
PHENIXrefinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 5CEH

5ceh


Resolution: 3.05→34.54 Å / SU ML: 0.51 / Cross valid method: FREE R-VALUE / σ(F): 2 / Phase error: 32.84
RfactorNum. reflection% reflection
Rfree0.2898 2383 5.09 %
Rwork0.2318 --
obs0.2348 46807 92.34 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 873.18 Å2 / Biso mean: 104.7451 Å2 / Biso min: 35.84 Å2
Refinement stepCycle: final / Resolution: 3.05→34.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9312 0 92 14 9418
Biso mean--96.14 62.87 -
Num. residues----1180
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0079626
X-RAY DIFFRACTIONf_angle_d0.79813097
X-RAY DIFFRACTIONf_chiral_restr0.0451413
X-RAY DIFFRACTIONf_plane_restr0.0061693
X-RAY DIFFRACTIONf_dihedral_angle_d16.6245733
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 17

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.0352-3.09710.42821390.34442478261787
3.0971-3.16440.3871430.33642703284694
3.1644-3.2380.37851530.32052638279195
3.238-3.31890.37341520.30252644279694
3.3189-3.40850.39821320.29832700283294
3.4085-3.50870.35491270.28642508263589
3.5087-3.62190.36241270.31282291241882
3.6219-3.75120.4041390.32342826296599
3.7512-3.90120.31190.26342565268490
3.9012-4.07840.33471250.23512322244782
4.0784-4.29310.34131480.20762516266490
4.2931-4.56150.26981410.17822618275992
4.5615-4.91280.2391360.16932595273192
4.9128-5.40550.20061360.18482690282695
5.4055-6.18380.2341480.21082768291698
6.1838-7.77630.29611500.2172789293999
7.7763-34.54240.21341680.1862773294198
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)
12.17740.92830.98261.49640.30821.1855-0.26530.0143-0.9808-0.2881-0.0852-0.33840.24390.3486-0.04360.7239-0.1201-0.07480.5279-0.05270.5847-50.352831.94168.373
21.1354-2.0795-0.51911.24791.5932-0.42730.1623-0.317-0.15480.4155-0.11-0.52250.2213-0.026500.5846-0.04860.15430.86410.05290.8631-56.044262.890633.3665
31.6474-0.3366-0.2821.50080.60211.24620.0209-0.1689-0.0132-0.04730.06790.1810.0721-0.1282-0.00010.5084-0.1424-0.05240.56340.01780.4634-52.599245.420319.2506
40.5187-0.1139-0.44341.5012-1.11842.22070.03160.62440.6536-0.2753-0.03970.1874-0.6979-0.1686-0.00041.0612-0.0694-0.01870.93680.230.926-54.770363.8218-4.7231
50.26820.2969-0.21580.2684-0.26020.39350.4441-0.5943-0.16470.2224-0.69041.4394-1.60760.24960.01251.1058-0.0234-0.1670.70560.17871.4889-57.561473.83583.6851
61.94161.17730.06230.9592-0.30010.0973-0.39430.2265-0.1031-1.53140.80470.7213-0.30310.5742-0.00031.93820.02990.02121.22950.24760.7147-50.87154.3085-14.4369
71.8112-0.50010.0221.03650.16020.81030.05840.0781-0.0849-0.12640.1194-0.1179-0.09450.3541-0.00020.482-0.1092-0.0740.65760.0230.4483-12.019769.841911.3903
80.5808-0.17840.45070.21720.11820.8078-0.72570.9106-1.2408-1.18450.4378-0.1480.4598-0.2994-0.00390.8487-0.21210.19250.712-0.03280.9332-31.347882.2093-8.4174
90.28420.046-0.38140.4991-0.4860.16410.27170.9799-0.112-0.3004-0.06851.5084-0.15540.10240.0171.3111-0.40810.29590.5950.1111.4202-40.06683.9718-5.0443
102.77720.5406-0.82554.1145-0.45092.5495-0.04920.2080.2337-0.23460.0841-0.0703-0.01060.07770.00020.3435-0.0498-0.10750.6405-0.02380.375-11.22565.411410.7217
113.11920.3556-1.2652.52150.30721.9490.2411-0.5620.95110.6441-0.04830.4963-0.4985-0.28290.00250.65530.02340.07870.8447-0.07250.7084-22.598976.496829.3419
122.68170.8329-1.19641.56860.90781.8258-0.4691-1.35790.49240.64590.56270.1481-0.0433-0.42510.00030.92820.16150.15941.2236-0.19840.8731-25.958876.07938.6181
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 12 through 64 )A12 - 64
2X-RAY DIFFRACTION2chain 'A' and (resid 65 through 165 )A65 - 165
3X-RAY DIFFRACTION3chain 'A' and (resid 166 through 604 )A166 - 604
4X-RAY DIFFRACTION4chain 'A' and (resid 605 through 674 )A605 - 674
5X-RAY DIFFRACTION5chain 'A' and (resid 675 through 702 )A675 - 702
6X-RAY DIFFRACTION6chain 'A' and (resid 703 through 785 )A703 - 785
7X-RAY DIFFRACTION7chain 'B' and (resid 12 through 116 )B12 - 116
8X-RAY DIFFRACTION8chain 'B' and (resid 117 through 173 )B117 - 173
9X-RAY DIFFRACTION9chain 'B' and (resid 174 through 362 )B174 - 362
10X-RAY DIFFRACTION10chain 'B' and (resid 363 through 565 )B363 - 565
11X-RAY DIFFRACTION11chain 'B' and (resid 566 through 673 )B566 - 673
12X-RAY DIFFRACTION12chain 'B' and (resid 674 through 785 )B674 - 785

+
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