Structural insights into human peroxisome proliferator activated receptor delta (PPAR-delta) selective ligand binding.
Structural insights into human peroxisome proliferator activated receptor delta (PPAR-delta) selective ligand binding.
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对人过氧化物酶体增殖物激活受体三角洲（PPAR-DELTA）选择性配体结合的结构见解。
DOI：
10.1371/journal.pone.0033643
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Polikarpov I
中科院分区：
文献类型：
--
作者：
Batista FA;Trivella DB;Bernardes A;Gratieri J;Oliveira PS;Figueira AC;Webb P;Polikarpov I
过氧化物酶体增殖物激活受体（Peroxisome proliferator activated receptor，PPARs）是一类与脂肪酸和葡萄糖代谢密切相关的转录因子，在心脏疾病、炎症反应等过程中发挥着重要作用。几个研究小组开发了PPAR亚型特异性调节剂，以触发特定PPARs的期望效果，而没有与其他亚型激活相关的有害副作用。然而，目前，许多化合物，结合到一个的PPARs交叉反应与其他和合理的策略，以获得高选择性的PPAR调节剂还远不清楚。GW0742是一种合成配体，其与PPARδ的结合比与PPARα或PPARγ的结合紧密300倍以上，但PPARδ：GW0742相互作用的结构基础和强选择性的原因尚不清楚。本文报道了PPARδ：GW 0742复合物的晶体结构。将PPARδ：GW0742复合物与已发表的与α和γ选择性激动剂和泛激动剂复合的PPAR结构进行比较，表明埋藏的激素结合口袋中的两个残基（Val 312和Ile 328）在PPARδ选择性结合中发挥特殊作用，对这些残基中突变效应的实验和计算分析证实了这一点，并表明排列在PPARα和γ配体结合口袋中的大体积取代基是GW0742结合的结构屏障。该分析提出了选择性PPARδ配体设计的一般策略。
Peroxisome proliferator activated receptors (PPARs δ, α and γ) are closely related transcription factors that exert distinct effects on fatty acid and glucose metabolism, cardiac disease, inflammatory response and other processes. Several groups developed PPAR subtype specific modulators to trigger desirable effects of particular PPARs without harmful side effects associated with activation of other subtypes. Presently, however, many compounds that bind to one of the PPARs cross-react with others and rational strategies to obtain highly selective PPAR modulators are far from clear. GW0742 is a synthetic ligand that binds PPARδ more than 300-fold more tightly than PPARα or PPARγ but the structural basis of PPARδ:GW0742 interactions and reasons for strong selectivity are not clear. Here we report the crystal structure of the PPARδ:GW0742 complex. Comparisons of the PPARδ:GW0742 complex with published structures of PPARs in complex with α and γ selective agonists and pan agonists suggests that two residues (Val312 and Ile328) in the buried hormone binding pocket play special roles in PPARδ selective binding and experimental and computational analysis of effects of mutations in these residues confirms this and suggests that bulky substituents that line the PPARα and γ ligand binding pockets as structural barriers for GW0742 binding. This analysis suggests general strategies for selective PPARδ ligand design.
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影响因子：
3.5
作者：
Markt, Patrick;Schuster, Daniela;Langer, Thierry
通讯作者：
Langer, Thierry
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
64.8
作者：
Kersten, S;Desvergne, B;Wahli, W
通讯作者：
Wahli, W
影响因子：
64.8
作者：
Nolte, RT;Wisely, GB;Milburn, MV
通讯作者：
Milburn, MV
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH