6VZN

Crystal structure of human PPARgamma ligand binding domain Y473E mutant

Summary for 6VZN

• Entry DOI: 10.2210/pdb6vzn/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma (2 entities in total)
• Functional Keywords: nuclear receptors, tzds, drug design, therapeutic targets, translation
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 62830.92

Authors

Shang, J.,Kojetin, D.J. (deposition date: 2020-02-28, release date: 2021-03-03, Last modification date: 2023-10-11)

Primary citation

Shang, J.,Kojetin, D.J.
Structural mechanism underlying ligand binding and activation of PPAR gamma.
Structure, 29:940-950.e4, 2021

PubMed Abstract: Ligands bind to an occluded orthosteric ligand-binding pocket within the nuclear receptor ligand-binding domain. Molecular simulations have revealed theoretical ligand entry/exit pathways to the orthosteric pocket; however, it remains unclear whether ligand binding proceeds through induced fit or conformational selection mechanisms. Here, using nuclear magnetic resonance spectroscopy, isothermal titration calorimetry, and surface plasmon resonance analysis, we provide evidence that structurally distinct agonists bind peroxisome proliferator-activated receptor γ (PPARγ) via a two-step induced fit mechanism involving an initial fast kinetic step followed by a slow conformational change. The agonist encounter complex binding pose is suggested in crystal structures where ligands bind to a surface pore suggested as a ligand entry site in molecular simulations. Our findings suggest an activation mechanism for PPARγ whereby agonist binding occurs through an initial encounter complex followed by a transition of the ligand into the final binding pose within the orthosteric pocket, inducing a transcriptionally active conformation.

PubMed: 33713599
DOI: 10.1016/j.str.2021.02.006

Experimental method

X-RAY DIFFRACTION (2.3 Å)