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Yorodumi- EMDB-27025: CRYO-EM STRUCTURE OF HUMAN 15-PGDH IN COMPLEX WITH SMALL MOLECULE... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-27025 | |||||||||
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Title | CRYO-EM STRUCTURE OF HUMAN 15-PGDH IN COMPLEX WITH SMALL MOLECULE SW222746 | |||||||||
Map data | ||||||||||
Sample |
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Keywords | DEHYDROGENASE / INHIBITOR / OXIDOREDUCTASE / OXIDOREDUCTASE-INHIBITOR complex | |||||||||
Function / homology | Function and homology information 15-hydroxyprostaglandin dehydrogenase (NAD+) / 15-hydroxyicosatetraenoate dehydrogenase / 15-hydroxyprostaglandin dehydrogenase (NAD+) activity / regulation of prostaglandin catabolic process / ductus arteriosus closure / ovulation / prostaglandin E receptor activity / thrombin-activated receptor signaling pathway / Biosynthesis of Lipoxins (LX) / parturition ...15-hydroxyprostaglandin dehydrogenase (NAD+) / 15-hydroxyicosatetraenoate dehydrogenase / 15-hydroxyprostaglandin dehydrogenase (NAD+) activity / regulation of prostaglandin catabolic process / ductus arteriosus closure / ovulation / prostaglandin E receptor activity / thrombin-activated receptor signaling pathway / Biosynthesis 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 | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
Authors | Huang W / Taylor DJ | |||||||||
Funding support | United States, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_27025.map.gz | 32.2 MB | EMDB map data format | |
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Header (meta data) | emd-27025-v30.xml emd-27025.xml | 15.3 KB 15.3 KB | Display Display | EMDB header |
Images | emd_27025.png | 104.4 KB | ||
Filedesc metadata | emd-27025.cif.gz | 5.5 KB | ||
Others | emd_27025_half_map_1.map.gz emd_27025_half_map_2.map.gz | 59.5 MB 59.5 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-27025 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-27025 | HTTPS FTP |
-Validation report
Summary document | emd_27025_validation.pdf.gz | 777.9 KB | Display | EMDB validaton report |
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Full document | emd_27025_full_validation.pdf.gz | 777.5 KB | Display | |
Data in XML | emd_27025_validation.xml.gz | 11.9 KB | Display | |
Data in CIF | emd_27025_validation.cif.gz | 14.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-27025 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-27025 | HTTPS FTP |
-Related structure data
Related structure data | 8cwlMC 8cvnC 8fd8C C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_27025.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.02 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_27025_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_27025_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : HUMAN 15-PGDH IN COMPLEX WITH INHIBITOR
Entire | Name: HUMAN 15-PGDH IN COMPLEX WITH INHIBITOR |
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Components |
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-Supramolecule #1: HUMAN 15-PGDH IN COMPLEX WITH INHIBITOR
Supramolecule | Name: HUMAN 15-PGDH IN COMPLEX WITH INHIBITOR / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: 15-hydroxyprostaglandin dehydrogenase [NAD(+)]
Macromolecule | Name: 15-hydroxyprostaglandin dehydrogenase [NAD(+)] / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: 15-hydroxyprostaglandin dehydrogenase (NAD+) |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 27.747906 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: 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 UniProtKB: 15-hydroxyprostaglandin dehydrogenase [NAD(+)] |
-Macromolecule #2: 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE
Macromolecule | Name: 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / type: ligand / ID: 2 / Number of copies: 2 / Formula: NAI |
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Molecular weight | Theoretical: 665.441 Da |
Chemical component information | ChemComp-NAI: |
-Macromolecule #3: 2-methyl-6-[7-(piperidine-1-carbonyl)quinoxalin-2-yl]isoquinolin-...
Macromolecule | Name: 2-methyl-6-[7-(piperidine-1-carbonyl)quinoxalin-2-yl]isoquinolin-1(2H)-one type: ligand / ID: 3 / Number of copies: 2 / Formula: RLD |
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Molecular weight | Theoretical: 398.457 Da |
Chemical component information | ChemComp-RLD: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.08 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.25 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |