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- EMDB-27010: CRYO-EM STRUCTURE OF HUMAN 15-PGDH IN COMPLEX WITH SMALL MOLECULE... -

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Basic information

Entry
Database: EMDB / ID: EMD-27010
TitleCRYO-EM STRUCTURE OF HUMAN 15-PGDH IN COMPLEX WITH SMALL MOLECULE SW209415
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-[butyl(oxidanyl)-$l^{3}-sulfanyl]-4-(2,3-dimethylimidazol-4-yl)-6-(1,3-thiazol-2-yl)thieno[2,3-b]pyridin-3-amine
KeywordsDEHYDROGENASE / INHIBITOR / OXIDOREDUCTASE / OXIDOREDUCTASE-INHIBITOR complex
Function / homology
Function and homology information


15-hydroxyprostaglandin dehydrogenase (NAD+) / 15-hydroxyicosatetraenoate dehydrogenase / regulation of prostaglandin catabolic process / ductus arteriosus closure / thrombin-activated receptor signaling pathway / ovulation / 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 / thrombin-activated receptor signaling pathway / ovulation / 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: 2.4 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 18, 2022-
Header (metadata) releaseMar 1, 2023-
Map releaseMar 1, 2023-
UpdateJun 12, 2024-
Current statusJun 12, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27010.png

Downloads & links

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Map

FileDownload / File: emd_27010.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.52 Å
Density
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.094779916 - 0.34692636
Average (Standard dev.)-0.00006672243 (±0.004888958)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 266.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_27010_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_27010_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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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-[butyl(oxidanyl)-$l^{3}-sulfanyl]-4-(2,3-dimethylimidazol-4-yl)-6-(1,3-thiazol-2-yl)thieno[2,3-b]pyridin-3-amine

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

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

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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: 27.886053 KDa
Recombinant expressionOrganism: Escherichia coli-Pichia pastoris shuttle vector pPpARG4 (others)
SequenceString: HMVNGKVALV TGAAQGIGRA FAEALLLKGA KVALVDWNLE AGVQCKAALD EQFEPQKTLF IQCDVADQQQ LRDTFRKVVD HFGRLDILV NNAGVNNEKN WEKTLQINLV SVISGTYLGL DYMSKQNGGE GGIIINMSSL AGLMPVAQQP VYCASKHGIV G FTRSAALA ...String:
HMVNGKVALV TGAAQGIGRA FAEALLLKGA KVALVDWNLE AGVQCKAALD EQFEPQKTLF IQCDVADQQQ LRDTFRKVVD HFGRLDILV NNAGVNNEKN WEKTLQINLV SVISGTYLGL DYMSKQNGGE GGIIINMSSL AGLMPVAQQP VYCASKHGIV G FTRSAALA ANLMNSGVRL NAICPGFVNT AILESIEKEE NMGQYIEYKD HIKDMIKYYG ILDPPLIANG LITLIEDDAL NG AIMKITT SKGIHFQDY

UniProtKB: 15-hydroxyprostaglandin dehydrogenase [NAD(+)]

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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

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Macromolecule #3: 2-[butyl(oxidanyl)-$l^{3}-sulfanyl]-4-(2,3-dimethylimidazol-4-yl)...

MacromoleculeName: 2-[butyl(oxidanyl)-$l^{3}-sulfanyl]-4-(2,3-dimethylimidazol-4-yl)-6-(1,3-thiazol-2-yl)thieno[2,3-b]pyridin-3-amine
type: ligand / ID: 3 / Number of copies: 2 / Formula: SWL
Molecular weightTheoretical: 433.614 Da
Chemical component information

ChemComp-SWL:
2-[butyl(oxidanyl)-$l^{3}-sulfanyl]-4-(2,3-dimethylimidazol-4-yl)-6-(1,3-thiazol-2-yl)thieno[2,3-b]pyridin-3-amine

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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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

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Image processing #1

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 776110
Image processing ID1

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Image processing #2

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 776110
Image processing ID2

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