SMBP Group Meeting: Justin Lindsay

Tuesday Jun 4, 2024, 2:00 PM → 3:00 PM America/New_York

3rd Floor Classroom (162)

Speaker: Justin Lindsay
 
Topic: What contact analysis can reveal about ligand binding of nuclear hormone receptors

Abstract: Here, I present a series of studies applying contact analysis to investigate structural properties of nuclear hormone receptors (NRs). The first is an investigation of the mechanisms of allostery underlying cooperative and anti-cooperative binding of the Retinoid X receptor with two cognate NRs, thyroid hormone receptor (TR) and constitutive androstane receptor (CAR). The second study examines the protein-ligand contacts that differentiate agonist and inverse-agonist binding to the ligand binding domain (LBD) of RORy (retinoid acid receptor-related orphan nuclear receptor). Using crystal structures of RORy bound to 125 different ligands, we identify contacts differentiating active and inactive states of the LBD. Additionally, we use MD simulation to identify interactions characteristic of constitutive NR activity, crucially including those between helices 11 and 12. Lastly, I compare and contrast contact analysis methods commonly applied to proteins and chromatin to identify what each method can reveal about the dynamics of either biomolecule. Using NRs as a test case we apply a contact PCA variant typically used to identify regions of active and inactive chromatin from chromosome interaction data to proteins, which we find reports the consensus features, making it promising for the study of semi-structured proteins. We apply our CAMERRA contact analysis method to HI-C and microscopy data of chromosome 21 to isolate the dominant motions. Applying this same method to a collection of Hi-C data across the human blood cell lineage reveals the elements of chromatin structure which most heavily differentiate these cell types.