PROJECT ABSTRACT
Improved Targeting of Somatostatin Receptors for Pediatric Conditions
Gigantism is a childhood developmental disorder whereby abnormally high levels of growth hormone result
in excessive growth in both height and girth. The disorder can have serious physical complications including
diabetes and loss of vision as well as social isolation. In the majority of cases gigantism is caused by pituitary
adenomas which, when surgery is not an option, is treated with somatostatin receptor agonists to suppress
growth hormone levels and provide symptom relief. Somatostatin receptors (SSTRs) are G protein coupled
receptors (GPCRs) highly expressed in pituitary adenomas. Two analogues of the endogenous peptide,
octreotide and lanreotide, were originally developed as SSTR2-selective, long-lasting peptide therapeutics for
gigantism and other conditions. While they have proved successful, long-term side effects and other suboptimal
properties drive the need for improved pharmaceutical interventions for gigantism. Much remains unknown about
SSTRs and their pharmacology. To date, I have determined structures of SSTR2, however some questions of
subtype selectivity remain unanswered without structures of the other subtypes. Much of the additional
information about SSTR signaling partners is based upon downstream cellular assays, and much remains
unknown about the relevance of SSTR subtype selectivity and signaling partner bias. Here I propose to utilize a
combination of structural characterization with cryogenic electron microscopy (cryoEM), molecular dynamics
simulations, and biochemical assays in order to characterize the selectivity, activation, and signaling profiles of
SSTRs. The work will build upon my existing skillset in molecular simulations, modelling, and protein
biochemistry while providing invaluable training in cryoEM data collection/processing and cell-based biochemical
assays. Successful completion of this work will provide critical insight into the signaling landscape of the
somatostatin receptor and the structural basis for both ligand-based and SSTR-subtype-based G protein
selectivity. This will bridge several gaps in knowledge of SSTRs that should help in the development of improved,
small molecule therapeutics that do not require repeated injections in children.