Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor γ
Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor γ
复制标题
DOI：
10.1074/jbc.m702538200
复制
发表时间：
2007-06-22
影响因子：
4.8
通讯作者：
Garratt, Richard C.
中科院分区：
文献类型：
--
作者：
Ambrosio, Andre L. B.;Dias, Sandra M. G.;Garratt, Richard C.
Ajulemic acid（AJA）是THC-11-oic acid的合成类似物，THC-11-oic acid是四氢大麻酚（THC）的代谢物，THC是来自植物大麻的娱乐性药物大麻的主要活性成分。AJA在体内具有有效的镇痛和抗炎活性，但没有THC的精神作用。然而，其确切的作用机制仍然未知。生物化学研究表明，AJA直接和选择性地结合过氧化物酶体增殖物激活受体（PPAR γ）的同种型γ，这表明这可能是该化合物的一种神经元相关受体，也是治疗疼痛和炎症的药物开发的潜在靶点。在这里，我们报告的晶体结构的配体结合结构域的γ同种型的人过氧化物酶体增殖体激活受体在复杂的阿佳酸，确定在2.8埃的分辨率。我们的研究结果表明，与其他已知的部分激动剂的过氧化物酶体增殖物激活受体，解释其适度激活的结合模式，以及同种型选择性的结构基础，如先前在体外观察到的。该结构还提供了线索，部分激动本身的理解，建议一个合理的方法来设计的分子能够激活受体的水平，避免不良的副作用。
Ajulemic acid (AJA) is a synthetic analog of THC-11-oic acid, a metabolite of tetrahydrocannabinol (THC), the major active ingredient of the recreational drug marijuana derived from the plant Cannabis sativa. AJA has potent analgesic and anti-inflammatory activity in vivo, but without the psychotropic action of THC. However, its precise mechanism of action remains unknown. Biochemical studies indicate that AJA binds directly and selectively to the isotype gamma of the peroxisome proliferator-activated receptor (PPAR gamma) suggesting that this may be a pharmacologically relevant receptor for this compound and a potential target for drug development in the treatment of pain and inflammation. Here, we report the crystal structure of the ligand binding domain of the gamma isotype of human PPAR in complex with ajulemic acid, determined at 2.8-angstrom resolution. Our results show a binding mode that is compatible with other known partial agonists of PPAR, explaining their moderate activation of the receptor, as well as the structural basis for isotype selectivity, as observed previously in vitro. The structure also provides clues to the understanding of partial agonism itself, suggesting a rational approach to the design of molecules capable of activating the receptor at levels that avoid undesirable side effects.