Structural highlights
Function
PDE3B_HUMAN Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. May play a role in fat metabolism. Regulates cAMP binding of RAPGEF3. Through simultaneous binding to RAPGEF3 and PIK3R6 assembles a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.[1] [2]
Publication Abstract from PubMed
Boronic acid inhibitors often undergo nucleophilic addition upon binding to an enzyme due to the electrophilicity of the boron atom. A new class of boronic acid inhibitors of human phosphodiesterase 3B (PDE3B) has recently been disclosed, along with the 2.7 A-resolution crystal structure of PDE3B complexed with inhibitor GSK4394835A [Rowley et al. (2024) Discovery and SAR study of boronic acid-based selective PDE3B inhibitors from a novel DNA-encoded library. J. Med. Chem. 67, 2049-2065]. The crystal structure shows the binding of an intact, unreacted boronic acid, but discrepancies were evident in refinement statistics. Accordingly, we redetermined the structure using structure factor amplitudes deposited in the Protein Data Bank (accession code 8SYC), showing that the boronic acid moiety of GSK4394835A undergoes nucleophilic attack by H737 to form a tetrahedral boronate anion. We refined the structure to convergence with excellent refinement statistics, concluding that GSK4394835A is a reversible covalent inhibitor of PDE3B.
Covalent Binding of the Boronic Acid-Based Inhibitor GSK4394835A to Phosphodiesterase 3B, a Drug Target for Cardiovascular Disease.,Eaton SA, Christianson DW J Med Chem. 2025 Dec 25;68(24):26574-26578. doi: 10.1021/acs.jmedchem.5c03081. , Epub 2025 Dec 2. PMID:41331906[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wilson LS, Baillie GS, Pritchard LM, Umana B, Terrin A, Zaccolo M, Houslay MD, Maurice DH. A phosphodiesterase 3B-based signaling complex integrates exchange protein activated by cAMP 1 and phosphatidylinositol 3-kinase signals in human arterial endothelial cells. J Biol Chem. 2011 May 6;286(18):16285-96. doi: 10.1074/jbc.M110.217026. Epub 2011, Mar 10. PMID:21393242 doi:10.1074/jbc.M110.217026
- ↑ Scapin G, Patel SB, Chung C, Varnerin JP, Edmondson SD, Mastracchio A, Parmee ER, Singh SB, Becker JW, Van der Ploeg LH, Tota MR. Crystal structure of human phosphodiesterase 3B: atomic basis for substrate and inhibitor specificity. Biochemistry. 2004 May 25;43(20):6091-100. PMID:15147193 doi:10.1021/bi049868i
- ↑ Eaton SA, Christianson DW. Covalent Binding of the Boronic Acid-Based Inhibitor GSK4394835A to Phosphodiesterase 3B, a Drug Target for Cardiovascular Disease. J Med Chem. 2025 Dec 25;68(24):26574-26578. PMID:41331906 doi:10.1021/acs.jmedchem.5c03081
