LB-FP-4 Dual crystal structures of Steroidogenic Factor-1 complexed with PIP2 and PIP3 reveal independent modes of inositol headgroup coordination

Program: Late-Breaking Abstracts
Session: SAT-LB-Late-Breaking Poster Session 1
Bench to Bedside
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-LB-05
Raymond D Blind*1, Holly A Ingraham1, Robert Fletterick2, Elena P Sablin3 and Debanu Das4
1University of California San Francisco, San Francisco, CA, 2Univ of CA - San Francisco, San Francisco, CA, 3University of California San Francisco, 4Joint Center for Structural Genomics, Stanford Synchrotron Radiation Lightsource
Steroidogenic Factor-1 (SF-1, NR5A1) is a nuclear receptor with essential endocrine functions in steroidogenic tissues in adults and throughout development. Prior work by our group has shown this transcription factor interacts with both phosphatidylinositol (4,5) bisphosphate (PIP2) & (3,4,5) triphosphate (PIP3), but atomic resolution details of how these potent signaling lipids bind SF-1 remain unclear. Here, we report two crystal structures of the human SF-1 ligand binding domain complexed to PIP2 and PIP3 at 3.0Å resolution, both co-crystallized with a peptide corresponding to the coactivator PGC-1α. Initial examination of electron-density maps corresponding to the PIP2 and PIP3-bound structures reveals novel electron densities that define the ligand positions, demonstrating how the head groups of PIP2 and PIP3 are coordinated by SF-1. Previous studies suggested PIP3 might be registered by SF-1 residues in regions that correspond with human SF-1 mutations associated with 46 X,Y sex reversal in patients. We are currently refining the models to define any unique coordination features of these ligands by the receptor. These data, coupled with follow-up functional studies, should reveal how these signaling phospholipids bind and regulate SF-1.

Nothing to Disclose: RDB, HAI, RF, EPS, DD

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NCI Grant 1K01CA172957 to RDB