Research


Ongoing efforts are focused on the following three inter-related projects:

Delineating protein kinase design principles using evolutionary-systems approaches

Protein kinases are exquisitely designed molecular machines that display remarkable diversity and complexity in their mechanisms of action. We are mining the wealth of evolutionary information embedded in protein kinase sequences from diverse organisms to obtain an in-depth understanding of the evolutionary rules that govern the structure and regulation of these proteins. Important goals are to quantify the sequence similarities and differences between functionally divergent kinases using statistical and computational approaches, and to experimentally test the role of evolutionarily constrained motifs using biochemical and biophysical techniques. We are also conceptualizing protein kinase knowledge in the form of ontology to facilitate systems level analysis of protein kinase data.

Selected publications:


Predicting the functional impact of cancer mutations in protein kinases

Large scale cancer genome sequencing studies are beginning to reveal the mutational profiles of the 518 protein kinase genes encoded in the human genome from many different cancer types. A detailed understanding of the structural and functional impact of these mutations can potentially lead to new therapies for cancer. We are integrating and analyzing diverse forms of protein kinase data to identify key causative mutations in the cancer kinome. We are using selected receptor tyrosine kinases as our experimental system to predict and test the impact of cancer mutations. We are also developing a computational framework for rapid and consistent annotations of protein kinase mutations identified in cancer genome sequencing studies.

Selected publications:


Understanding the divergence and adaptation of protein kinases in apicomplexan parasites

Apicomplexa is an evolutionary divergent phylum of eukaryotic pathogens responsible for human and agricultural diseases. Many cellular functions in apicomplexans are controlled by protein kinases, which have emerged as promising targets for infectious diseases. We are interested in understanding how parasitic kinases structurally and mechanistically differ from their eukaryotic hosts. To this end, we are systematically identifying and classifying kinase sequences in apicomplexan genomes and performing quantitative comparisons of parasite and host kinase sequences and structures. We are also involved in various collaborative efforts to identify and characterize apicomplexan protein kinase substrates.

Selected publications: