The signaling phosphatidylinositol lipids PI(4,5)P2 (PIP2) and PI (3,4,5)P3 (PIP3) bind to the nuclear receptor 5A family (NR5As), but their regulatory mechanisms remain unknown. The crystal structures of human NR5A1 (steroidogenic factor-1, SF-1) ligand binding domain (LBD) bound to PIP2 and PIP3 show the lipid hydrophobic tails sequestered in the hormone pocket, as predicted. However, unlike classic nuclear receptor hormones, the phosphoinositide headgroups are fully solvent exposed and complete the LBD fold by organizing the receptor architecture at the hormone pocket entrance.

 

The highest affinity phosphoinositide ligand PIP3 stabilizes the coactivator binding groove and increases coactivator pepide recruitment. This receptor-ligand topology defines a previously unidentified regulatory protein-lipid surface on SF-1 with the phosphoinositide head group at its nexus and poised to interact with other proteins. This surface on SF-1 coincides with the predicted binding site of the corepressor DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region on chromosome X), and importantly harbors missense mutations associated with human endocrine disorders. Our data provide the structural basis for this poorly understood cluster of human SF-1 mutations and demonstrates how signaling phosphoinositides function as regulatory ligands for NR5As.

Phoebe Ahn - Undergraduate Researcher (Vandy Class of 2020)

Structural analyses of novel nuclear receptor/phospholipid complexes.

                                                                                       

Hometown -  Chicago, IL

Major in Chemistry

Major in Medicine Health & Society

Major in Spanish 

Pre-medical Student, Vanderbilt University College of Arts & Sciences

 

 

The Journal of Biological Chemistry Herb Tabor Award to Ray Blind Vanderbilt University.
ACS Res Scholar.png
Untitled.png
National Cancer Institute Transition to Indepedence Award to Ray Blind Vanderbilt University
National Institute of General Medical Sciences Institutional Research and Career Development Fellowship to Ray Blind, Vanderbilt University
Vanderbilt Diabetes Research and Training Center
Vanderbilt Ingram Cancer Center
Vanderbilt Institute of Chemical Biology
Vanderbilt Center for Structural Biology
  • 125px-vanderbilt_university_wordmark-svg.png
  • ghat.png
  • LinkedIn Basic
  • YouTube Basic
  • Twitter Basic

© 2019  Ray Blind