Peroxisome proliferator-activated receptor (PPAR ) belongs to the thyroid hormone receptor-like nuclear receptor subfamily 1, which is one of the ligand-activated transcription factors. PPAR forms a heterodimer with retinoid X receptors (RXRs), recruits coactivators, and then binds to the cognate peroxisome proliferative response elements on target genes. PPAR is a good therapeutic target for type 2 diabetes mellitus, as well as other metabolic diseases including obesity and atherosclerosis.
This section compares experimental and numerical data on the effect of R288A substitution in PPAR on imatinib binding and analyzes the effect of R288A substitution on dimer complex affinity changes. Imatinib is a specific tyrosine kinase receptor inhibitor that is used in the therapy of Philadelphia chromosome-positive chronic myelogenous leukemia and gastrointestinal stromal tumors, both of which are marked by an abnormal, constitutively expressed tyrosine kinase that causes unregulated cell growth. This section of the article will analyze the substitution of R288A in PPAR° when binding with imatinib.
Fig. 1 shows the three-dimensional structure of such a PPAR°-imatinib complex. The following graph b)-c) shows the combined experimental and calculated graphs for the replacement of R288A in the Human PPARgamma protein when it binds to imatinib and the effect of this replacement on the affinity of the dimer complex. Experimental
data are shown in red and calculated data are shown in blue. As stated earlier, the direction of changes in affinity for the calculated and experimental plots in our studies are directional. Thus, a decrease in Kd and lg(cond(W)) values, when R288A is replaced with PPAR°, leads to an increase in the affinity of the PPAR°-imatinib dimer complex