Project Summary
The sense of smell provides animals with vital information about their environment. At the molecular level,
olfactory stimuli consist of thousands of distinct small molecules that share no common chemical feature other
than being volatile. To contend with this diversity, insects and mammals alike have evolved large families of
olfactory receptors (ORs) that operate in a combinatorial way, whereby some receptors are broadly activated by
many different odorants and others are exquisitely tuned to a specific compound. The molecular mechanisms
that endow ORs with such diverse ligand-binding properties remain unknown, largely because the isolation and
structural characterization of ORs has been a decades-long technological challenge. Using cryo-electron
microscopy, I recently determined the first atomic-resolution structure of an insect OR bound to an odor. By
determining the structures of additional insect ORs with broad and specific ligand-binding properties, the
proposed research project will elucidate the molecular mechanism of odor detection and discrimination.
To this end, the K99 mentored phase (Aim 1) will reveal the atomic structures of two primitive insect ORs with
different ligand specificities unbound and in complex with multiple odor ligands, shedding light on the molecular
determinants that underlie broad or specific odor selectivity. Next, the R00 independent phase (Aim 2) will focus
on ORs from disease-carrying mosquitoes that participate in human host-seeking. These ORs exhibit small
polymorphisms that drastically affect their ability to detect human odors. Elucidation of the atomic structure of
these mosquito ORs bound to human volatiles will illuminate the molecular properties that enable mosquitoes to
detect and prey on humans. Together, this research program will lend fundamental insight into the normal
function of sensory processing of olfactory information. Additionally, as insect ORs are critically involved in
human host-seeking that facilitates the spread of insect-borne diseases, this work will provide a foundation for
the development of novel insect repellents that could curb diseases such as malaria, Zika, and dengue fever.
The proposed development plan complements my training in structural biology and biophysics with
computational modeling of receptor-ligand interactions and in vivo assays in Drosophila. At the end of the
mentored phase, I will be equipped with the necessary tools to conduct comprehensive structural and functional
studies of odor detection and discrimination by insect vectors of disease. To achieve these goals, I will take
advantage of the extensive resources of the Rockefeller University, the mentorship of Dr. Vanessa Ruta and the
appointment of an Advisory Committee that will lend expertise in key aspects of the project and career
development. Additionally, with the support and resources from the MOSAIC/UE5 network I will expand my
mentorship and leadership skills to successfully transition to an independent position while continuing my
ongoing efforts to enhance diversity in the biomedical workforce.