[English] 日本語
Yorodumi
- EMDB-27025: Cryo-EM structure of Human 15-PGDH in complex with small molecule... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-27025
TitleCryo-EM structure of Human 15-PGDH in complex with small molecule SW222746
Map data
Sample
  • Complex: HUMAN 15-PGDH IN COMPLEX WITH INHIBITOR
    • Protein or peptide: 15-hydroxyprostaglandin dehydrogenase [NAD(+)]
  • Ligand: 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE
  • Ligand: 2-methyl-6-[7-(piperidine-1-carbonyl)quinoxalin-2-yl]isoquinolin-1(2H)-one
Function / homology
Function and homology information


15-hydroxyprostaglandin dehydrogenase (NAD+) / 15-hydroxyicosatetraenoate dehydrogenase / regulation of prostaglandin catabolic process / ductus arteriosus closure / ovulation / thrombin-activated receptor signaling pathway / prostaglandin E receptor activity / 15-hydroxyprostaglandin dehydrogenase (NAD+) activity / Synthesis of Lipoxins (LX) / parturition ...15-hydroxyprostaglandin dehydrogenase (NAD+) / 15-hydroxyicosatetraenoate dehydrogenase / regulation of prostaglandin catabolic process / ductus arteriosus closure / ovulation / thrombin-activated receptor signaling pathway / prostaglandin E receptor activity / 15-hydroxyprostaglandin dehydrogenase (NAD+) activity / Synthesis of Lipoxins (LX) / parturition / lipoxygenase pathway / Biosynthesis of D-series resolvins / Biosynthesis of E-series 18(S)-resolvins / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / Oxidoreductases; Acting on the CH-OH group of donors; With NAD+ or NADP+ as acceptor / oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor / prostaglandin metabolic process / negative regulation of cell cycle / NAD+ binding / positive regulation of vascular associated smooth muscle cell proliferation / transforming growth factor beta receptor signaling pathway / kidney development / female pregnancy / NAD binding / response to estradiol / basolateral plasma membrane / response to ethanol / response to lipopolysaccharide / positive regulation of apoptotic process / extracellular exosome / nucleoplasm / identical protein binding / cytosol / cytoplasm
Similarity search - Function
short chain dehydrogenase / Short-chain dehydrogenase/reductase, conserved site / Short-chain dehydrogenases/reductases family signature. / Short-chain dehydrogenase/reductase SDR / NAD(P)-binding domain superfamily
Similarity search - Domain/homology
15-hydroxyprostaglandin dehydrogenase [NAD(+)]
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsHuang W / Taylor DJ
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1RM1GM142002 United States
CitationJournal: Nat Commun / Year: 2023
Title: Small molecule inhibitors of 15-PGDH exploit a physiologic induced-fit closing system.
Authors: Wei Huang / Hongyun Li / Janna Kiselar / Stephen P Fink / Sagar Regmi / Alexander Day / Yiyuan Yuan / Mark Chance / Joseph M Ready / Sanford D Markowitz / Derek J Taylor /
Abstract: 15-prostaglandin dehydrogenase (15-PGDH) is a negative regulator of tissue stem cells that acts via enzymatic activity of oxidizing and degrading PGE2, and related eicosanoids, that support stem ...15-prostaglandin dehydrogenase (15-PGDH) is a negative regulator of tissue stem cells that acts via enzymatic activity of oxidizing and degrading PGE2, and related eicosanoids, that support stem cells during tissue repair. Indeed, inhibiting 15-PGDH markedly accelerates tissue repair in multiple organs. Here we have used cryo-electron microscopy to solve the solution structure of native 15-PGDH and of 15-PGDH individually complexed with two distinct chemical inhibitors. These structures identify key 15-PGDH residues that mediate binding to both classes of inhibitors. Moreover, we identify a dynamic 15-PGDH lid domain that closes around the inhibitors, and that is likely fundamental to the physiologic 15-PGDH enzymatic mechanism. We furthermore identify two key residues, F185 and Y217, that act as hinges to regulate lid closing, and which both inhibitors exploit to capture the lid in the closed conformation, thus explaining their sub-nanomolar binding affinities. These findings provide the basis for further development of 15-PGDH targeted drugs as therapeutics for regenerative medicine.
History
DepositionMay 19, 2022-
Header (metadata) releaseMar 8, 2023-
Map releaseMar 8, 2023-
UpdateMar 8, 2023-
Current statusMar 8, 2023Processing site: RCSB / Status: Released

-
Structure visualization

Supplemental images

emd_27025.png

Downloads & links

-
Map

FileDownload / File: emd_27025.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.02 Å
Density
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.18514256 - 1.1554935
Average (Standard dev.)-0.00013666098 (±0.011040748)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 261.12 Å
α=β=γ: 90.0 °

-
Supplemental data

-
Half map: #2

Fileemd_27025_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #1

Fileemd_27025_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : HUMAN 15-PGDH IN COMPLEX WITH INHIBITOR

EntireName: HUMAN 15-PGDH IN COMPLEX WITH INHIBITOR
Components
  • Complex: HUMAN 15-PGDH IN COMPLEX WITH INHIBITOR
    • Protein or peptide: 15-hydroxyprostaglandin dehydrogenase [NAD(+)]
  • Ligand: 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE
  • Ligand: 2-methyl-6-[7-(piperidine-1-carbonyl)quinoxalin-2-yl]isoquinolin-1(2H)-one

-
Supramolecule #1: HUMAN 15-PGDH IN COMPLEX WITH INHIBITOR

SupramoleculeName: HUMAN 15-PGDH IN COMPLEX WITH INHIBITOR / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

-
Macromolecule #1: 15-hydroxyprostaglandin dehydrogenase [NAD(+)]

MacromoleculeName: 15-hydroxyprostaglandin dehydrogenase [NAD(+)] / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: 15-hydroxyprostaglandin dehydrogenase (NAD+)
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.747906 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MVNGKVALVT GAAQGIGRAF AEALLLKGAK VALVDWNLEA GVQCKAALDE QFEPQKTLFI QCDVADQQQL RDTFRKVVDH FGRLDILVN NAGVNNEKNW EKTLQINLVS VISGTYLGLD YMSKQNGGEG GIIINMSSLA GLMPVAQQPV YCASKHGIVG F TRSAALAA ...String:
MVNGKVALVT GAAQGIGRAF AEALLLKGAK VALVDWNLEA GVQCKAALDE QFEPQKTLFI QCDVADQQQL RDTFRKVVDH FGRLDILVN NAGVNNEKNW EKTLQINLVS VISGTYLGLD YMSKQNGGEG GIIINMSSLA GLMPVAQQPV YCASKHGIVG F TRSAALAA NLMNSGVRLN AICPGFVNTA ILESIEKEEN MGQYIEYKDH IKDMIKYYGI LDPPLIANGL ITLIEDDALN GA IMKITTS KGIHFQDY

-
Macromolecule #2: 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE

MacromoleculeName: 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / type: ligand / ID: 2 / Number of copies: 2 / Formula: NAI
Molecular weightTheoretical: 665.441 Da
Chemical component information

ChemComp-NAI:
1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / Nicotinamide adenine dinucleotide

-
Macromolecule #3: 2-methyl-6-[7-(piperidine-1-carbonyl)quinoxalin-2-yl]isoquinolin-...

MacromoleculeName: 2-methyl-6-[7-(piperidine-1-carbonyl)quinoxalin-2-yl]isoquinolin-1(2H)-one
type: ligand / ID: 3 / Number of copies: 2 / Formula: RLD
Molecular weightTheoretical: 398.457 Da
Chemical component information

ChemComp-RLD:
2-methyl-6-[7-(piperidine-1-carbonyl)quinoxalin-2-yl]isoquinolin-1(2H)-one

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

-
Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.25 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.08 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

-
Image processing #1

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 361366
Image processing ID1

-
Image processing #2

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 361366
Image processing ID2

+
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