[English] 日本語
Yorodumi
- PDB-6f78: Potent and selective Aldo-Keto Reductase 1C3 (AKR1C3) inhibitors ... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 6f78
TitlePotent and selective Aldo-Keto Reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: Application of a Bioisosteric Scaffold Hopping Approach to Flufenamic acid
ComponentsAldo-keto reductase family 1 member C3
KeywordsOXIDOREDUCTASE / aldo-keto reductase 1C3 / AKR1C3 / 17betaHSD5 / Prostate cancer / CRPC / bioisosterism / scaffold hopping / inhibitors
Function / homology
Function and homology information


prostaglandin-F synthase / testosterone 17beta-dehydrogenase (NADP+) / prostaglandin D2 11-ketoreductase activity / ketoreductase activity / prostaglandin-F synthase activity / cellular response to prostaglandin stimulus / cellular response to corticosteroid stimulus / 15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity / 3beta(or 20alpha)-hydroxysteroid dehydrogenase / negative regulation of retinoic acid biosynthetic process ...prostaglandin-F synthase / testosterone 17beta-dehydrogenase (NADP+) / prostaglandin D2 11-ketoreductase activity / ketoreductase activity / prostaglandin-F synthase activity / cellular response to prostaglandin stimulus / cellular response to corticosteroid stimulus / 15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity / 3beta(or 20alpha)-hydroxysteroid dehydrogenase / negative regulation of retinoic acid biosynthetic process / 3alpha(17beta)-hydroxysteroid dehydrogenase (NAD+) / 5alpha-androstane-3beta,17beta-diol dehydrogenase activity / delta4-3-oxosteroid 5beta-reductase activity / farnesol catabolic process / geranylgeranyl reductase activity / 3alpha-hydroxysteroid 3-dehydrogenase / phenanthrene 9,10-monooxygenase activity / macromolecule metabolic process / regulation of testosterone biosynthetic process / cellular response to jasmonic acid stimulus / 3alpha(or 20beta)-hydroxysteroid dehydrogenase / androstan-3-alpha,17-beta-diol dehydrogenase activity / dihydrotestosterone 17-beta-dehydrogenase activity / androsterone dehydrogenase activity / testosterone dehydrogenase (NAD+) activity / testosterone biosynthetic process / RA biosynthesis pathway / regulation of retinoic acid receptor signaling pathway / cellular response to prostaglandin D stimulus / ketosteroid monooxygenase activity / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / retinal metabolic process / testosterone 17-beta-dehydrogenase (NADP+) activity / progesterone metabolic process / 17beta-estradiol 17-dehydrogenase / estradiol 17-beta-dehydrogenase [NAD(P)] activity / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / aldo-keto reductase (NADPH) activity / cyclooxygenase pathway / all-trans-retinol dehydrogenase (NAD+) activity / prostaglandin H2 endoperoxidase reductase activity / positive regulation of endothelial cell apoptotic process / all-trans-retinol dehydrogenase (NADP+) activity / Oxidoreductases; Acting on the CH-OH group of donors; With NAD+ or NADP+ as acceptor / daunorubicin metabolic process / doxorubicin metabolic process / oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor / retinal dehydrogenase activity / bile acid binding / aldose reductase (NADPH) activity / retinoid metabolic process / prostaglandin metabolic process / renal absorption / steroid metabolic process / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Retinoid metabolism and transport / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / keratinocyte differentiation / cellular response to calcium ion / cellular response to starvation / response to nutrient / male gonad development / positive regulation of reactive oxygen species metabolic process / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / G protein-coupled receptor signaling pathway / positive regulation of cell population proliferation / extracellular exosome / nucleus / cytosol / cytoplasm
Similarity search - Function
Aldo-keto reductase family 1 member C / Aldo/keto reductase family putative active site signature. / Aldo/keto reductase family signature 1. / NADP-dependent oxidoreductase domain / Aldo/keto reductase family signature 2. / Aldo/keto reductase, conserved site / Aldo-keto reductase / NADP-dependent oxidoreductase domain / Aldo/keto reductase family / NADP-dependent oxidoreductase domain superfamily ...Aldo-keto reductase family 1 member C / Aldo/keto reductase family putative active site signature. / Aldo/keto reductase family signature 1. / NADP-dependent oxidoreductase domain / Aldo/keto reductase family signature 2. / Aldo/keto reductase, conserved site / Aldo-keto reductase / NADP-dependent oxidoreductase domain / Aldo/keto reductase family / NADP-dependent oxidoreductase domain superfamily / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
Chem-CVN / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Aldo-keto reductase family 1 member C3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsGoyal, P. / Wahlgren, W.Y. / Friemann, R.
Funding support Sweden, 1items
OrganizationGrant numberCountry
Sweden
CitationJournal: Eur J Med Chem / Year: 2018
Title: Potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a bioisosteric scaffold hopping approach to flufenamic acid.
Authors: Pippione, A.C. / Carnovale, I.M. / Bonanni, D. / Sini, M. / Goyal, P. / Marini, E. / Pors, K. / Adinolfi, S. / Zonari, D. / Festuccia, C. / Wahlgren, W.Y. / Friemann, R. / Bagnati, R. / ...Authors: Pippione, A.C. / Carnovale, I.M. / Bonanni, D. / Sini, M. / Goyal, P. / Marini, E. / Pors, K. / Adinolfi, S. / Zonari, D. / Festuccia, C. / Wahlgren, W.Y. / Friemann, R. / Bagnati, R. / Boschi, D. / Oliaro-Bosso, S. / Lolli, M.L.
History
DepositionDec 7, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 4, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 11, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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 / _citation_author.name
Revision 1.2Jan 17, 2024Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Aldo-keto reductase family 1 member C3
B: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,8938
Polymers72,6112
Non-polymers2,2826
Water12,484693
1
A: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4474
Polymers36,3061
Non-polymers1,1413
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4474
Polymers36,3061
Non-polymers1,1413
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)47.203, 49.151, 83.386
Angle α, β, γ (deg.)73.97, 86.68, 69.80
Int Tables number1
Space group name H-MP1

-
Components

#1: Protein Aldo-keto reductase family 1 member C3 / 17-beta-hydroxysteroid dehydrogenase type 5 / 17-beta-HSD 5 / 3-alpha-HSD type II / brain / 3-alpha- ...17-beta-hydroxysteroid dehydrogenase type 5 / 17-beta-HSD 5 / 3-alpha-HSD type II / brain / 3-alpha-hydroxysteroid dehydrogenase type 2 / 3-alpha-HSD type 2 / Chlordecone reductase homolog HAKRb / Dihydrodiol dehydrogenase 3 / DD3 / Dihydrodiol dehydrogenase type I / HA1753 / Indanol dehydrogenase / Prostaglandin F synthase / PGFS / Testosterone 17-beta-dehydrogenase 5 / Trans-1 / 2-dihydrobenzene-1 / 2-diol dehydrogenase


Mass: 36305.547 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKR1C3, DDH1, HSD17B5, KIAA0119, PGFS / Production host: Escherichia coli (E. coli)
References: UniProt: P42330, Oxidoreductases, 3alpha-hydroxysteroid 3-dehydrogenase, indanol dehydrogenase, prostaglandin-F synthase, 3alpha(17beta)-hydroxysteroid dehydrogenase (NAD+), testosterone ...References: UniProt: P42330, Oxidoreductases, 3alpha-hydroxysteroid 3-dehydrogenase, indanol dehydrogenase, prostaglandin-F synthase, 3alpha(17beta)-hydroxysteroid dehydrogenase (NAD+), testosterone 17beta-dehydrogenase (NADP+), trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
#2: Chemical ChemComp-CVN / 4-[[3,5-bis(trifluoromethyl)phenyl]amino]-1,2-benzoxazol-3-one


Mass: 362.227 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H8F6N2O2
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE / Nicotinamide adenine dinucleotide phosphate


Mass: 743.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 693 / 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: 2.4 Å3/Da / Density % sol: 48.78 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 100mM MES pH 6.0, 25% PEG 8000

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 7, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.3→80.11 Å / Num. obs: 156106 / % possible obs: 93.9 % / Redundancy: 7.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.05 / Rrim(I) all: 0.053 / Net I/σ(I): 18.6
Reflection shellResolution: 1.3→1.37 Å

-
Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
XDSdata reduction
SCALAdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ry0

1ry0


Resolution: 1.3→44.37 Å / SU ML: 0.09 / Cross valid method: FREE R-VALUE / σ(F): 1.97 / Phase error: 17.93 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1694 7756 4.97 %
Rwork0.1431 --
obs0.1444 155912 93.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.3→44.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5106 0 148 694 5948
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0065473
X-RAY DIFFRACTIONf_angle_d0.9667449
X-RAY DIFFRACTIONf_dihedral_angle_d9.0483304
X-RAY DIFFRACTIONf_chiral_restr0.082798
X-RAY DIFFRACTIONf_plane_restr0.005950
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3-1.31470.19232390.15854882X-RAY DIFFRACTION92
1.3147-1.33020.19132560.14514752X-RAY DIFFRACTION91
1.3302-1.34640.1942770.14394873X-RAY DIFFRACTION92
1.3464-1.36350.19942380.14084786X-RAY DIFFRACTION91
1.3635-1.38140.17712870.13574846X-RAY DIFFRACTION93
1.3814-1.40030.18152170.13484816X-RAY DIFFRACTION91
1.4003-1.42030.17161950.12584947X-RAY DIFFRACTION93
1.4203-1.44150.18262370.13084826X-RAY DIFFRACTION91
1.4415-1.46410.15972490.13254883X-RAY DIFFRACTION93
1.4641-1.48810.18542690.12594909X-RAY DIFFRACTION93
1.4881-1.51370.15592450.12294862X-RAY DIFFRACTION94
1.5137-1.54130.16052630.12254954X-RAY DIFFRACTION93
1.5413-1.57090.17162990.12084908X-RAY DIFFRACTION94
1.5709-1.6030.14022410.11844900X-RAY DIFFRACTION94
1.603-1.63780.15012760.12524946X-RAY DIFFRACTION93
1.6378-1.67590.17352340.1274913X-RAY DIFFRACTION93
1.6759-1.71790.16852530.1324830X-RAY DIFFRACTION92
1.7179-1.76430.15482390.12955034X-RAY DIFFRACTION95
1.7643-1.81620.16672710.13855016X-RAY DIFFRACTION95
1.8162-1.87480.17682650.14174986X-RAY DIFFRACTION95
1.8748-1.94190.15512810.14334975X-RAY DIFFRACTION95
1.9419-2.01960.16592680.14044957X-RAY DIFFRACTION95
2.0196-2.11150.15032880.14324958X-RAY DIFFRACTION94
2.1115-2.22280.17652590.14554986X-RAY DIFFRACTION95
2.2228-2.36210.16982630.1515055X-RAY DIFFRACTION96
2.3621-2.54450.192880.15865065X-RAY DIFFRACTION97
2.5445-2.80050.16592880.15385039X-RAY DIFFRACTION96
2.8005-3.20560.16752740.15634965X-RAY DIFFRACTION94
3.2056-4.03830.1742670.14485143X-RAY DIFFRACTION98
4.0383-44.39550.16852300.13955144X-RAY DIFFRACTION97

+
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