Due to Dr. Blumberg's retirement, this project was completed in January 2018. The lab described the critical role of Trp-588 of presynaptic Munc13-1 played for ligand binding and membrane translocation. In addition, they found that the deletion of the C26 methyl substituent from the bryostatin analogue Merle 23 has negligible impact on its biological profile and potency. The team described the potential for the design of custom C1 domain targeted molecules selective for the atypical C1 domains of Vav family proteins. Finally, they showed the importance of the REM (Ras exchange) domain for membrane interactions by RasGRP3.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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Basic Sciences
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Cooke, Mariana; Zhou, Xiaoling; Casado-Medrano, Victoria et al. (2018) Characterization of AJH-836, a diacylglycerol-lactone with selectivity for novel PKC isozymes. J Biol Chem 293:8330-8341
Das, Joydip; Kedei, Noemi; Kelsey, Jessica S et al. (2018) Critical Role of Trp-588 of Presynaptic Munc13-1 for Ligand Binding and Membrane Translocation. Biochemistry 57:732-741
Czikora, Agnes; Pany, Satyabrata; You, Youngki et al. (2018) Structural determinants of phorbol ester binding activity of the C1a and C1b domains of protein kinase C theta. Biochim Biophys Acta Biomembr 1860:1046-1056
Cummins, Thomas J; Kedei, Noemi; Czikora, Agnes et al. (2018) Synthesis and Biological Evaluation of Fluorescent Bryostatin Analogues. Chembiochem 19:877-889
Zhao, Xiguang; Kedei, Noemi; Michalowski, Alexandra et al. (2018) Deletion of the C26 Methyl Substituent from the Bryostatin Analogue Merle?23 Has Negligible Impact on Its Biological Profile and Potency. Chembiochem 19:1049-1059
Kelsey, Jessica S; Géczy, Tamás; Kaler, Christopher J et al. (2017) The C1 domain of Vav3, a novel potential therapeutic target. Cell Signal 40:133-142
Ohashi, Nami; Kobayashi, Ryosuke; Nomura, Wataru et al. (2017) Synthesis and Evaluation of Dimeric Derivatives of Diacylglycerol-Lactones as Protein Kinase C Ligands. Bioconjug Chem 28:2135-2144
Pearce, Larry V; Ann, Jihyae; Jung, Aeran et al. (2017) Novel Radiolabeled Vanilloid with Enhanced Specificity for Human Transient Receptor Potential Vanilloid 1 (TRPV1). J Med Chem 60:8246-8252
Lee, Sunho; Kang, Dong Wook; Ryu, HyungChul et al. (2017) t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists. Bioorg Med Chem 25:2451-2462
Elhalem, Eleonora; Donadío, Lucía Gandolfi; Zhou, Xiaoling et al. (2017) Exploring the influence of indololactone structure on selectivity for binding to the C1 domains of PKC?, PKC?, and RasGRP. Bioorg Med Chem 25:2971-2980

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