[English] 日本語
Yorodumi
- PDB-6p5m: Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]p... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 6p5m
TitleDiscovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based Cdc7 inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Anti-Tumor Agent
ComponentsRho-associated protein kinase 2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Inhibitor / Oral / Anti-tumor / TRANSFERASE-TRANSFERASE INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


cellular response to acetylcholine / positive regulation of connective tissue growth factor production / positive regulation of amyloid precursor protein catabolic process / positive regulation of centrosome duplication / regulation of angiotensin-activated signaling pathway / Rho-dependent protein serine/threonine kinase activity / negative regulation of protein localization to lysosome / regulation of keratinocyte differentiation / positive regulation of connective tissue replacement / positive regulation of fibroblast growth factor production ...cellular response to acetylcholine / positive regulation of connective tissue growth factor production / positive regulation of amyloid precursor protein catabolic process / positive regulation of centrosome duplication / regulation of angiotensin-activated signaling pathway / Rho-dependent protein serine/threonine kinase activity / negative regulation of protein localization to lysosome / regulation of keratinocyte differentiation / positive regulation of connective tissue replacement / positive regulation of fibroblast growth factor production / positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process / response to transforming growth factor beta / negative regulation of myosin-light-chain-phosphatase activity / regulation of nervous system process / regulation of cell junction assembly / negative regulation of bicellular tight junction assembly / regulation of protein metabolic process / modulation by host of viral process / regulation of cellular response to hypoxia / positive regulation of protein localization to early endosome / embryonic morphogenesis / negative regulation of nitric oxide biosynthetic process / negative regulation of biomineral tissue development / cellular response to testosterone stimulus / actomyosin structure organization / regulation of establishment of endothelial barrier / RHO GTPases Activate ROCKs / regulation of stress fiber assembly / regulation of cell motility / Sema4D induced cell migration and growth-cone collapse / aortic valve morphogenesis / response to angiotensin / regulation of establishment of cell polarity / RHOBTB1 GTPase cycle / cortical actin cytoskeleton organization / regulation of focal adhesion assembly / RHOB GTPase cycle / positive regulation of amyloid-beta formation / tau-protein kinase activity / EPHA-mediated growth cone collapse / mRNA destabilization / positive regulation of cardiac muscle hypertrophy / RHOC GTPase cycle / RHOH GTPase cycle / centrosome duplication / mitotic cytokinesis / Rho protein signal transduction / smooth muscle contraction / RHOA GTPase cycle / epithelial to mesenchymal transition / canonical NF-kappaB signal transduction / regulation of cell adhesion / positive regulation of stress fiber assembly / EPHB-mediated forward signaling / blood vessel diameter maintenance / negative regulation of angiogenesis / positive regulation of endothelial cell migration / response to ischemia / protein localization to plasma membrane / regulation of actin cytoskeleton organization / peptidyl-threonine phosphorylation / tau protein binding / regulation of circadian rhythm / cytoplasmic ribonucleoprotein granule / small GTPase binding / VEGFA-VEGFR2 Pathway / rhythmic process / G alpha (12/13) signalling events / actin cytoskeleton organization / peptidyl-serine phosphorylation / Potential therapeutics for SARS / positive regulation of MAPK cascade / cytoskeleton / non-specific serine/threonine protein kinase / positive regulation of cell migration / positive regulation of protein phosphorylation / negative regulation of gene expression / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / positive regulation of gene expression / structural molecule activity / RNA binding / ATP binding / metal ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / Rho-associated protein kinase 2, HR1 domain / ROCK, Rho binding domain / Rho-associated protein kinase 1/2 / Rho Binding / Rho-binding (RhoBD) domain profile. / HR1 rho-binding domain / REM-1 domain profile. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) ...: / Rho-associated protein kinase 2, HR1 domain / ROCK, Rho binding domain / Rho-associated protein kinase 1/2 / Rho Binding / Rho-binding (RhoBD) domain profile. / HR1 rho-binding domain / REM-1 domain profile. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PH-like domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-O1S / Rho-associated protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 Å
AuthorsHoffman, I.D. / Skene, R.J.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based Cdc7 Inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Antitumor Agent.
Authors: Kurasawa, O. / Miyazaki, T. / Homma, M. / Oguro, Y. / Imada, T. / Uchiyama, N. / Iwai, K. / Yamamoto, Y. / Ohori, M. / Hara, H. / Sugimoto, H. / Iwata, K. / Skene, R. / Hoffman, I. / Ohashi, ...Authors: Kurasawa, O. / Miyazaki, T. / Homma, M. / Oguro, Y. / Imada, T. / Uchiyama, N. / Iwai, K. / Yamamoto, Y. / Ohori, M. / Hara, H. / Sugimoto, H. / Iwata, K. / Skene, R. / Hoffman, I. / Ohashi, A. / Nomura, T. / Cho, N.
History
DepositionMay 30, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 15, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Rho-associated protein kinase 2
B: Rho-associated protein kinase 2
C: Rho-associated protein kinase 2
D: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)185,5016
Polymers184,8704
Non-polymers6312
Water81145
1
A: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,5332
Polymers46,2171
Non-polymers3151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,5332
Polymers46,2171
Non-polymers3151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Rho-associated protein kinase 2


Theoretical massNumber of molelcules
Total (without water)46,2171
Polymers46,2171
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Rho-associated protein kinase 2


Theoretical massNumber of molelcules
Total (without water)46,2171
Polymers46,2171
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
A: Rho-associated protein kinase 2
D: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,7503
Polymers92,4352
Non-polymers3151
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4250 Å2
ΔGint-27 kcal/mol
Surface area36760 Å2
MethodPISA
6
B: Rho-associated protein kinase 2
C: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,7503
Polymers92,4352
Non-polymers3151
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4050 Å2
ΔGint-26 kcal/mol
Surface area36520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.456, 146.416, 111.876
Angle α, β, γ (deg.)90.000, 97.120, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLYGLYARGARGAA23 - 41711 - 405
21GLYGLYARGARGBB19 - 4127 - 405
12PROPROTYRTYRAA18 - 4166 - 404
22PROPROTYRTYRCC18 - 4166 - 404
13PROPROTYRTYRAA18 - 4166 - 404
23PROPROTYRTYRDD18 - 4166 - 404
14SERSERARGARGBB17 - 4125 - 405
24GLYGLYARGARGCC21 - 4179 - 405
15SERSERARGARGBB17 - 4125 - 405
25GLYGLYARGARGDD21 - 4179 - 405
16PROPROARGARGCC18 - 4176 - 405
26PROPROARGARGDD18 - 4176 - 405

NCS ensembles :
ID
1
2
3
4
5
6

-
Components

#1: Protein
Rho-associated protein kinase 2 / Rho kinase 2 / Rho-associated / coiled-coil-containing protein kinase 2 / coiled-coil-containing ...Rho kinase 2 / Rho-associated / coiled-coil-containing protein kinase 2 / coiled-coil-containing protein kinase II / ROCK-II / p164 ROCK-2


Mass: 46217.484 Da / Num. of mol.: 4 / Fragment: UNP residues 18-417 / Mutation: F270Y
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ROCK2, KIAA0619 / Production host: unidentified baculovirus
References: UniProt: O75116, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-O1S / 6-(5-methyl-1H-pyrazol-4-yl)-2-[(pyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one


Mass: 315.393 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H17N5OS
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 45 / 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: 4.01 Å3/Da / Density % sol: 69.31 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.1 / Details: 0.8 M trisodium citrate, 0.1 M citrate, pH 5.1

-
Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.97648 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 3, 2011
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97648 Å / Relative weight: 1
ReflectionResolution: 2.65→50 Å / Num. obs: 83024 / % possible obs: 99.9 % / Redundancy: 4.2 % / Rmerge(I) obs: 0.103 / Χ2: 1.003 / Net I/σ(I): 9.1 / Num. measured all: 346085
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.65-2.73.90.78840941.085199.3
2.7-2.7440.72541311.001199.8
2.74-2.84.10.63641570.991100
2.8-2.854.20.55441230.9861100
2.85-2.924.20.43941440.9921100
2.92-2.984.30.36541500.9851100
2.98-3.064.30.30241330.9921100
3.06-3.144.30.25141010.9751100
3.14-3.234.30.21441630.9881100
3.23-3.344.30.17341561.0251100
3.34-3.464.20.14341341.0151100
3.46-3.64.30.11441511.0031100
3.6-3.764.20.09341531.0081100
3.76-3.964.20.08341320.9931100
3.96-4.214.20.07241731.0151100
4.21-4.534.10.06941551.0031100
4.53-4.994.10.06941651.0091100
4.99-5.714.10.06141660.9861100
5.71-7.1940.05741861.027199.9
7.19-504.10.03742570.9871100

-
Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.8.0238refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2F2U

2f2u


Resolution: 2.65→25 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.926 / SU B: 21.833 / SU ML: 0.2 / SU R Cruickshank DPI: 0.3557 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.356 / ESU R Free: 0.245
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.225 4128 5 %RANDOM
Rwork0.1934 ---
obs0.195 78660 99.05 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 181.37 Å2 / Biso mean: 57.52 Å2 / Biso min: 26.71 Å2
Baniso -1Baniso -2Baniso -3
1-2.15 Å2-0 Å23.07 Å2
2---2.38 Å2-0 Å2
3----0.51 Å2
Refinement stepCycle: final / Resolution: 2.65→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12694 0 44 45 12783
Biso mean--59.67 43.53 -
Num. residues----1574
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01313064
X-RAY DIFFRACTIONr_bond_other_d0.0010.01711940
X-RAY DIFFRACTIONr_angle_refined_deg1.3281.64317660
X-RAY DIFFRACTIONr_angle_other_deg1.1751.58227695
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.16851565
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.59322.462727
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.831152248
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.3581581
X-RAY DIFFRACTIONr_chiral_restr0.0630.21595
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214617
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022864
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A120330.09
12B120330.09
21A118700.11
22C118700.11
31A118540.11
32D118540.11
41B119190.1
42C119190.1
51B118350.11
52D118350.11
61C124770.07
62D124770.07
LS refinement shellResolution: 2.643→2.711 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.354 263 -
Rwork0.31 5282 -
all-5545 -
obs--90.72 %
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)
12.64981.16391.53171.58292.13653.73680.0055-0.27550.2769-0.02880.0428-0.2086-0.48590.0206-0.04830.26550.044-0.0740.0793-0.05310.2584-26.477555.1003-39.2834
22.0282-0.62850.30632.60240.96511.68470.02780.1246-0.196-0.0029-0.26220.5579-0.0981-0.26270.23440.20960.0391-0.04750.134-0.07660.213-54.161554.04-47.2019
32.16561.76881.36381.95961.91223.8951-0.12250.1916-0.3417-0.35860.1191-0.08430.1846-0.2250.00340.4781-0.044-0.04980.0903-0.00220.1661-10.129322.2079-16.1397
40.77880.0991-1.15052.2914-0.63433.08310.02520.005-0.02010.057-0.01080.157-0.1335-0.023-0.01440.16080.0335-0.01340.03750.01760.0297-12.583523.49312.7804
51.5257-1.27870.75031.5664-1.54562.9841-0.0049-0.1593-0.18160.26560.01270.05970.06090.0812-0.00780.4814-0.1127-0.07740.07640.00220.116-27.539321.4213-36.6563
60.7324-0.3094-0.5672.33280.60892.65550.08530.024-0.041-0.1143-0.0835-0.20980.0285-0.0756-0.00180.16440.0017-0.01720.0377-0.01650.0633-22.284220.7021-64.3358
72.3593-1.37111.10551.7258-1.81182.65640.00760.128-0.1501-0.05780.01720.2648-0.1688-0.1962-0.02480.18950.0122-0.07610.0567-0.05770.1622-13.570855.9585-16.1416
81.77360.41350.12892.0692-0.37921.4164-0.0209-0.2361-0.22550.0973-0.0666-0.2282-0.07870.21570.08750.1198-0.0135-0.03980.09270.02790.069214.743957.3454-11.2099
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A18 - 173
2X-RAY DIFFRACTION2A174 - 417
3X-RAY DIFFRACTION3B18 - 173
4X-RAY DIFFRACTION4B174 - 412
5X-RAY DIFFRACTION5C18 - 173
6X-RAY DIFFRACTION6C174 - 417
7X-RAY DIFFRACTION7D18 - 173
8X-RAY DIFFRACTION8D174 - 412

+
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