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- PDB-8cvn: Cryo-EM Structure of Human 15-PGDH in Complex with Small Molecule... -

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Basic information

Entry
Database: PDB / ID: 8cvn
TitleCryo-EM Structure of Human 15-PGDH in Complex with Small Molecule SW209415
Components15-hydroxyprostaglandin dehydrogenase [NAD(+)]
KeywordsOXIDOREDUCTASE / DEHYDROGENASE / INHIBITOR / OXIDOREDUCTASE-INHIBITOR complex
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
1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / Chem-SWL / 15-hydroxyprostaglandin dehydrogenase [NAD(+)]
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.4 Å
AuthorsHuang, W. / Taylor, D.J.
Funding support United States, 1items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 1, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 29, 2023Group: Database references / Category: pdbx_database_related

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 15-hydroxyprostaglandin dehydrogenase [NAD(+)]
B: 15-hydroxyprostaglandin dehydrogenase [NAD(+)]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,9706
Polymers55,7722
Non-polymers2,1984
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein 15-hydroxyprostaglandin dehydrogenase [NAD(+)] / 15-PGDH / Eicosanoid/docosanoid dehydrogenase [NAD(+)] / Prostaglandin dehydrogenase 1 / Short ...15-PGDH / Eicosanoid/docosanoid dehydrogenase [NAD(+)] / Prostaglandin dehydrogenase 1 / Short chain dehydrogenase/reductase family 36C member 1


Mass: 27886.053 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HPGD, PGDH1, SDR36C1
Production host: Escherichia coli-Pichia pastoris shuttle vector pPpARG4 (others)
References: UniProt: P15428, 15-hydroxyprostaglandin dehydrogenase (NAD+), Oxidoreductases; Acting on the CH-OH group of donors; With NAD+ or NADP+ as acceptor, 15-hydroxyicosatetraenoate dehydrogenase
#2: Chemical ChemComp-NAI / 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / NADH / Nicotinamide adenine dinucleotide


Mass: 665.441 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H29N7O14P2
#3: Chemical 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


Mass: 433.614 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H23N5OS3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: HUMAN 15-PGDH IN COMPLEX WITH INHIBITOR / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 250 nm
Image recordingElectron dose: 1.08 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Image processing
IDImage recording-ID
11
21
CTF correction
IDEM image processing-IDType
11PHASE FLIPPING AND AMPLITUDE CORRECTION
22PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstruction
IDResolution (Å)Resolution methodNum. of particlesImage processing-IDEntry-IDSymmetry type
12.4FSC 0.143 CUT-OFF77611018CVNPOINT
22.4FSC 0.143 CUT-OFF77611028CVNPOINT
RefinementHighest resolution: 2.4 Å

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