A new mode of inhibition

Abstract

Complementary structural biology approaches reveal how an agonist and a covalent inhibitor simultaneously bind to a nuclear receptor.

Keywords: PPARγ; antagonists; molecular biophysics; nuclear receptors; structural biology.

Figure 1.. Crystal structures of the PPARγ ligand-binding pocket.

When an agonist or a covalent inhibitor binds to PPARγ, it alters the structure of the ligand-binding pocket in PPARγ. The top left image shows the crystal structure of the PPARγ ligand-binding pocket (white) when bound to an agonist called MRL24 (light pink). The top right image shows the crystal structure of the PPARγ ligand-binding pocket when bound to T0070907 (light cyan), a covalent inhibitor that attaches via the amino acid Cys285. When MRL24 and T0070907 simultaneously bind to PPARγ, T0070907 is displaced (bottom left). The site where MRL24 sits in the PPARγ ligand-binding pocket overlaps with the site that T0070907 occupies (bottom right, black dashed ring). This clash causes the agonist (ML24) to displace the covalent inhibitor (T0070907) and shift it to a different position.