Rational discovery of a novel interface for a coactivator in the peroxisome proliferator‐activated receptor γ: Theoretical implications of impairment in type 2 diabetes mellitus

The peroxisome proliferator‐activated receptor γ (PPARγ) is important to adipocyte differentiation and glucose homeostasis, and mutations in the gene have been observed in type 2 diabetes mellitus. The mutated residues, V290 and P467, bind to neither ligands nor a coactivator peptide in the reported crystal structures of the PPARγ ligand binding domain. To understand the mechanism of type 2 diabetes mellitus caused by germline mutations in the PPARγ ligand‐binding domain, theoretical models of the PPARγ–ligand–coactivator complex were built at an atomic resolution. In the models, the secondary coactivator peptide was docked next to the conventional coactivator peptide, which both contain the LXXLL motif. The secondary interface in PPARγ for the secondary coactivator peptide has not been demonstrated by experiments. Binding energy calculations of the complex, considering the solvent effect, revealed that the secondary coactivator peptide, derived from nuclear receptor box 1 of steroid receptor coactivator 1, can be favorably bound to the secondary interface. The secondary coactivator peptide forms hydrogen bonds and a hydrophobic core with PPARγ and the primary coactivator peptide. Next, we applied mutations to PPARγ in silico and found that the V290M mutation, observed in type 2 diabetes mellitus, adversely affected the binding of the secondary peptide. Thus, our model provides structural insight into the impairment of PPARγ function in type 2 diabetes mellitus. Proteins 2005. © 2004 Wiley‐Liss, Inc.