Grant: Project Grant

Pancreatic, endocrine and cardiac tumours as well as intellectual disabilities and abnormal bone growth in children are caused by defective reading of the signal transmitted within cells by a messenger molecule called cyclic adenosine monophosphate (cAMP). Furthermore, a closely related molecule, cyclic guanosine monophosphate (cGMP), plays a critical role in the replication of the malaria parasite, Plasmodium falciparum. The goals of this project are to study two proteins that bind to cAMP and cGMP, i.e. the cAMP-dependent protein kinase A in mammals (PKA) and cGMP-dependent protein kinase G in P. falciparum (pfPKG), and to: (a) elucidate the structural and dynamical changes caused by inherited mutations that lead to incorrect translation of the cAMP signal and diseases such as cancer and developmental defects; (b) to understand how to suppress the signals carried by the cAMP and cGMP cyclic nucleotides to improve current cancer and malaria treatments. We will use nuclear magnetic resonance (NMR) spectroscopy to investigate how modified molecules that resemble cAMP and cGMP, and which may serve as future cancer and malaria drugs, interact with PKA and pfPKG, respectively. Their effects on these proteins are currently poorly understood at the structural and dynamical level, and NMR has only recently been used to investigate these interactions at atomic resolution. NMR will reveal the structural and dynamical changes in PKA and pfPKG caused by cAMP and cGMP analogs, respectively, as needed to fully understand how to modulate these proteins' activities. NMR is also ideally suited to unveil how disease-causing inherited mutations alter the physiological interactions of PKA with cAMP. Elucidating the structural and dynamical changes caused by disease-related mutations and modified cyclic nucleotides will help understand the molecular origins of multiple tumours and pediatric disorders, and will also facilitate the design of improved cancer and malaria drugs.