5WG8
Structure of PP5C with LB-100; 7-oxabicyclo[2.2.1]heptane-2,3-dicarbonyl moiety modeled in the density
Summary for 5WG8
| Entry DOI | 10.2210/pdb5wg8/pdb |
| Descriptor | Serine/threonine-protein phosphatase 5, MANGANESE (II) ION, (1S,2R,3S,4R)-3-(4-methylpiperazine-1-carbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid, ... (6 entities in total) |
| Functional Keywords | hydrolase inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 38501.55 |
| Authors | D'Arcy, B.M.,Swingle, M.R.,Honkanen, R.E.,Prakash, A. (deposition date: 2017-07-13, release date: 2018-07-18, Last modification date: 2023-10-04) |
| Primary citation | D'Arcy, B.M.,Swingle, M.R.,Papke, C.M.,Abney, K.A.,Bouska, E.S.,Prakash, A.,Honkanen, R.E. The Antitumor Drug LB-100 Is a Catalytic Inhibitor of Protein Phosphatase 2A (PPP2CA) and 5 (PPP5C) Coordinating with the Active-Site Catalytic Metals in PPP5C. Mol. Cancer Ther., 18:556-566, 2019 Cited by PubMed Abstract: LB-100 is an experimental cancer therapeutic with cytotoxic activity against cancer cells in culture and antitumor activity in animals. The first phase I trial (NCT01837667) evaluating LB-100 recently concluded that safety and efficacy parameters are favorable for further clinical testing. Although LB-100 is widely reported as a specific inhibitor of serine/threonine phosphatase 2A (PP2AC/), we could find no experimental evidence in the published literature demonstrating the specific engagement of LB-100 with PP2A , in cultured cells, or in animals. Rather, the premise for LB-100 targeting PP2AC is derived from studies that measure phosphate released from a phosphopeptide (K-R-pT-I-R-R) or inferred from the ability of LB-100 to mimic activity previously reported to result from the inhibition of PP2AC by other means. PP2AC and PPP5C share a common catalytic mechanism. Here, we demonstrate that the phosphopeptide used to ascribe LB-100 specificity for PP2A is also a substrate for PPP5C. Inhibition assays using purified enzymes demonstrate that LB-100 is a catalytic inhibitor of both PP2AC and PPP5C. The structure of PPP5C cocrystallized with LB-100 was solved to a resolution of 1.65Å, revealing that the 7-oxabicyclo[2.2.1]heptane-2,3-dicarbonyl moiety coordinates with the metal ions and key residues that are conserved in both PP2AC and PPP5C. Cell-based studies revealed some known actions of LB-100 are mimicked by the genetic disruption of These data demonstrate that LB-100 is a catalytic inhibitor of both PP2AC and PPP5C and suggest that the observed antitumor activity might be due to an additive effect achieved by suppressing both PP2A and PPP5C. PubMed: 30679389DOI: 10.1158/1535-7163.MCT-17-1143 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.65 Å) |
Structure validation
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