Reciprocal mutations in TM2/TM3 in a D2 dopamine receptor background confirms the importance of this microdomain as a selective determinant of para-halogenated 1,4-disubstituted aromatic piperazines.
Reciprocal mutations in TM2/TM3 in a D2 dopamine receptor background confirms the importance of this microdomain as a selective determinant of para-halogenated 1,4-disubstituted aromatic piperazines.
复制标题
D2 多巴胺受体背景中 TM2/TM3 的相互突变证实了该微结构域作为对卤代 1,4-二取代芳香族哌嗪的选择性决定因素的重要性。
DOI：
10.1002/ardp.200400993
复制
发表时间：
2005
影响因子：
5.1
通讯作者：
Schetz,JohnA
中科院分区：
文献类型：
--
作者：
Floresca,ChristinaZ;Chen,Shiuhwei;Kortagere,Sandhya;Schetz,JohnA
我们最近证明，在D4多巴胺受体中，跨越第二和第三跨膜（TM）结构域界面的芳香族微结构域影响具有1，4-二取代芳香族哌嗪/哌啶（1，4-DAP）结构的极D4选择性配体的高亲和力相互作用。基于其亚结构特征和对D4受体背景中构建的突变的敏感性模式，D4选择性1，4-DAP被分类为具有两种不同的结合模式，我们将其命名为模式1和模式3 [1]。在这里，我们通过测量在D2多巴胺受体背景中构建的相应的相互TM 2/TM 3突变对帕拉卤代模式1配体L750，667和FAUC 213的结合亲和力的影响，扩展了这些高D4选择性1，4-DAP的配体-受体结构-亲和力关系的发现。结果表明，D2-V2.61F+FV3.28 - 3.29LM突变体以显著增加的亲和力结合L750，667和FAUC 213，即，它的结合模式变得更像D4这些发现进一步支持了将包含位置2.61和3.28 - 3.29的TM 2/TM 3芳香族微域指定为1，4-DAP D4-选择性微域，并强调了芳香族化合物在该微域中的精确定位的重要性，这是L750，667和FAUC 213的选择性分子识别的关键。
We recently demonstrated that in the D4 dopamine receptor the aromatic microdomain that spans the interface of the second and third transmembrane (TM) domains influences the high affinity interactions of extremely D4‐selective ligands possessing a 1,4‐disubstituted aromatic piperazine/piperidine (1,4‐DAP) structure. On the basis of their substructural features and patterns of sensitivity to mutations constructed in a D4 receptor background, the D4‐selective 1,4‐DAPs were categorized as having two distinct modes of binding that we named mode‐1 and mode‐3 [1]. Here we extend these findings of the ligand‐receptor structure‐affinity relationships for some of these highly D4‐selective 1,4‐DAPs by measuring the effect of the corresponding reciprocal TM2/TM3 mutations constructed in a D2 dopamine receptor background on the binding affinity of the para‐halogenated mode‐1 ligands L750,667 and FAUC213. The results indicate that the D2‐V2.61F+FV3.28‐3.29LM mutant binds L750,667 and FAUC213 with significantly increased affinity, i.e., its binding profile becomes more D4‐like. These findings further support the assignment of the TM2/TM3 aromatic microdomain encompassing positions 2.61 and 3.28‐3.29 as a 1,4‐DAP D4‐selectivity microdomain and highlights the importance of the precise emplacement of aromatics in this microdomain as key to the selective molecular recognition of L750,667 and FAUC213.