Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor α/γ
Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor α/γ
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DOI：
10.1016/j.jsb.2015.07.006
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发表时间：
2015-09-01
影响因子：
3
通讯作者：
Polikarpov, Igor
中科院分区：
文献类型：
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作者：
dos Santos, Jademilson Celestino;Bernardes, Amanda;Polikarpov, Igor
过氧化物酶体激活受体（Peroxisome dispersivator-activated Receptors，PPARs）是一类配体依赖性转录因子，在人体内具有多种功能，包括调控糖和脂质代谢。PPAR γ是TZD激动剂的靶点，临床上用于改善胰岛素敏感性，而贝特类（PPAR α配体）可降低血清甘油三酯水平。我们在这里报告的结构研究GL 479，一个合成的双重PPAR α/γ激动剂，设计的氯贝酸骨架和苯二氮基部分的组合，作为生物电子等排取代芪基团，在复杂的PPAR α和PPAR γ受体。GL 479先前被报道为对两种PPARs具有高亲和力的PPARgamma的部分激动剂和PPARalpha的完全激动剂。我们的结构研究揭示了GL 479与PPARalpha和PPARgamma的不同结合模式，这可能解释了对每个受体观察到的不同激活行为。在这两种情况下，配体与位于螺旋12（H12）的Tyr相互作用，导致受体活性构象。在与PPARalpha的复合物中，GL 479占据了与其他完全激动剂观察到的配体结合口袋（LBP）相同的区域，而GL 479与PPARgamma结合显示出新的结合模式。我们的研究结果表明，PPARs LBP的一个新的区域，可用于设计部分激动剂以及双重PPAR α/γ激动剂，其联合收割机同时结合治疗胰岛素抵抗和血脂异常的治疗效果。(C)2015爱思唯尔公司All rights reserved.
Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-dependent transcription factors that control various functions in human organism, including the control of glucose and lipid metabolism. PPAR gamma is a target of TZD agonists, clinically used to improve insulin sensitivity whereas fibrates, PPAR alpha ligands, lower serum triglyceride levels. We report here the structural studies of GL479, a synthetic dual PPAR alpha/gamma agonist, designed by a combination of clofibric acid skeleton and a phenyldiazenyl moiety, as bioisosteric replacement of stilbene group, in complex with both PPAR alpha and PPAR gamma receptors. GL479 was previously reported as a partial agonist of PPAR gamma and a full agonist of PPAR alpha with high affinity for both PPARs. Our structural studies reveal different binding modes of GL479 to PPAR alpha and PPAR gamma, which may explain the distinct activation behaviors observed for each receptor. In both cases the ligand interacts with a Tyr located at helix 12 (H12), resulting in the receptor active conformation. In the complex with PPAR alpha, GL479 occupies the same region of the ligand-binding pocket (LBP) observed for other full agonists, whereas GL479 bound to PPAR gamma displays a new binding mode. Our results indicate a novel region of PPARs LBP that may be explored for the design of partial agonists as well dual PPAR alpha/gamma agonists that combine, simultaneously, the therapeutic effects of the treatment of insulin resistance and dyslipidemia. (C) 2015 Elsevier Inc. All rights reserved.