Research Projects

Heterotrimeric G-proteins (Gαβγ) are signal transducers that control cell behavior by regulating the flow of information from extracellular cues to intracellular effectors. Active G-protein coupled receptors (GPCRs) associate with guanosine diphosphate (GDP) bound inactive G-proteins, acting as guanosine exchange factors (GEFs) by facilitating the exchange of GDP for guanosine triphosphate (GTP) from the Gα subunit. Active G-proteins transduce various signals via interaction with their effector proteins, which can help develop therapeutic agents for various diseases. Guanine-nucleotide exchange modulators (GEMs) also influence G-protein signaling, with some having the ability to function as GEFs independent of GPCRs. The binding of non-GPCR GEFs to G-proteins differs from that of GPCRs, indicating different activation pathways. The Gα-binding and activating (GBA) motif is a critical structural component in the activity of these non-receptor GEFs. Dysregulation of canonical G-protein signaling by non-GPCR GEFs has been linked to various human diseases, emphasizing the importance of decoding the molecular mechanism of activation through non-GPCR modes. Further investigation into the structural and functional properties of GPCR and non-GPCR GEFs is necessary to fully realize their therapeutic potential. This proposal aims to understand the molecular-level activation of G-proteins through both GPCR and non-GPCR GEFs and how they affect conformational states via different binding interfaces.