TY - JOUR
T1 - Small molecule inhibitors of 15-PGDH exploit a physiologic induced-fit closing system
AU - Huang, Wei
AU - Li, Hongyun
AU - Kiselar, Janna
AU - Fink, Stephen P.
AU - Regmi, Sagar
AU - Day, Alexander
AU - Yuan, Yiyuan
AU - Chance, Mark
AU - Ready, Joseph M.
AU - Markowitz, Sanford D.
AU - Taylor, Derek J.
N1 - Funding Information:
We thank Dr. Hsin-Hsiung (Daniel) Tai for seminal contributions to understanding 15-PGDH and for help in establishing 15-PGDH enzyme kinetic assays. Computational support was provided by the Case Western Reserve University High Performance Computing Cluster. Anton 2 computer time was provided by the Pittsburgh Supercomputing Center (PSC) through Grant R01 GM116961 from the National Institutes of Health. The Anton 2 machine at PSC was generously made available by D.E. Shaw Research. Cryo-EM data were collected at, and sponsored by, the National Cancer Institute’s National Cryo-EM Facility at the Frederick National Laboratory for Cancer Research under contract HSSN261200800001E, the Midwest Consortium for High-Resolution Cryo-Electron Microscopy (U24 GM116789) and Cryo-EM pilot funds from Case Western Reserve University. This work was primarily supported by a grant from the NIH (RM1 GM142002 to D.J.T., S.D.M., & J.M.R.) and further supported by other NIH grants (R01 GM133841 and R01 CA240993 to D.J.T.; R35 CA197442 and P50 CA150964 to S.D.M.; R01 CA216863 to J.M.R. and S.D.M.; and U54 CA231649 to J.M.R.) and the Welch Foundation (I-1612 to J.M.R.).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-023-36463-7
DO - 10.1038/s41467-023-36463-7
M3 - Article
C2 - 36774348
AN - SCOPUS:85147835453
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 784
ER -