Waku Tsuyoshi, Shiraki Takuma, Oyama Takuji, Morikawa Kosuke
The Takara-Bio Endowed Division, Department of Biomolecular Recognition, Institute for Protein Research, Osaka University, Open Laboratories of Advanced Bioscience and Biotechnology, 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan.
FEBS Lett. 2009 Jan 22;583(2):320-4. doi: 10.1016/j.febslet.2008.12.017. Epub 2008 Dec 26.
15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) activates a nuclear receptor heterodimer, peroxisome proliferators-activated receptor gamma (PPARgamma)/ retinoid X receptor (RXRalpha) through covalent binding to Cys285 in PPARgamma ligand-binding domain (LBD). Here, we present the 1.9A crystal structure of C285S mutant LBD complexed with 15d-PGJ(2), corresponding to the non-covalently bound state. The ligand lies adjacent to a hydrogen-bond network around the helix H2 and the nearby beta-sheet. Comparisons with previous structures clarified the relationships between PPARgamma function and conformational alterations of LBD during the process of covalently binding ligands, such as 15d-PGJ(2), and thus suggested a mechanism, by which these ligands modulate PPARgamma/RXRalpha function through conformational changes of the loop following helix H2' and the beta-sheet.
15-脱氧-Δ¹²,¹⁴-前列腺素J₂（15d-PGJ₂）通过与过氧化物酶体增殖物激活受体γ（PPARγ）配体结合域（LBD）中的半胱氨酸285共价结合，激活核受体异二聚体，即过氧化物酶体增殖物激活受体γ（PPARγ）/视黄醇X受体（RXRα）。在此，我们展示了与15d-PGJ₂复合的C285S突变体LBD的1.9埃晶体结构，其对应于非共价结合状态。配体位于螺旋H2和附近β折叠周围的氢键网络附近。与先前结构的比较阐明了在共价结合配体（如15d-PGJ₂）过程中PPARγ功能与LBD构象改变之间的关系，从而提出了一种机制，即这些配体通过螺旋H2'之后的环和β折叠的构象变化来调节PPARγ/RXRα功能。
