Allosteric effects of the antipsychotic drug trifluoperazine on the energetics of calcium binding by calmodulin.
Allosteric effects of the antipsychotic drug trifluoperazine on the energetics of calcium binding by calmodulin.
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DOI：
10.1002/prot.22739
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发表时间：
2010-08-01
影响因子：
2.9
通讯作者：
Shea, Madeline A.
中科院分区：
文献类型：
--
作者：
Feldkamp, Michael D.;O'Donnell, Susan E.;Yu, Liping;Shea, Madeline A.
三氟拉嗪（TFP; Stelazine™）是钙调蛋白（CaM）的拮抗剂，钙调蛋白是钙依赖性信号转导的重要调节剂。关于TFP是否或在何处与载脂蛋白钙调素结合的报道各不相同。三种晶体结构（1CTR、1A 29、1 LIN）显示TFP以1、2或4 TFP/CaM的比例与（Ca 2+）4-CaM结合。在所有这些中，CaM结构域采用在具有增加的钙亲和力的CaM-激酶复合物中看到的“开放”构象。大多数研究表明，TFP也能增加钙调素的钙亲和力。为了比较TFP与apo CaM和（Ca 2+）4-CaM的结合，并探索对CaM的N-和C-结构域的不同影响，通过15 N-HSQC NMR监测CaM的化学计量TFP滴定。两个TFP结合载脂蛋白CaM，而四个结合（Ca ~（2+））~（4-）CaM。在这两种情况下，首选的网站是在C-结构域。在滴定过程中，一些共振的双相反应表明了位点间的相互作用。载脂蛋白CaM与（Ca ~（2+））_4-CaM的结合位点不同。在平衡钙滴定在规定的比例TFP：钙调素，TFP降低钙亲和力在大多数测试水平，这是类似于许多IQ-图案对钙调素的影响。然而，在测试的最高水平下，TFP提高了CaM N结构域的钙亲和力。提出了一个构象转换模型，以解释如何TFP可以发挥相反的变构效应的钙亲和力，通过结合到不同的网站在“封闭”，“半开放”和“开放”的结构域的钙调蛋白。在生理过程中，载脂蛋白钙调素，以及（钙2+）4-钙调素，需要考虑药物作用的潜在目标。
Trifluoperazine (TFP; Stelazine™) is an antagonist of calmodulin (CaM), an essential regulator of calcium-dependent signal transduction. Reports differ regarding whether, or where, TFP binds to apo CaM. Three crystallographic structures (1CTR, 1A29, 1LIN) show TFP bound to (Ca2+)4-CaM in ratios of 1, 2 or 4 TFP per CaM. In all of these, CaM domains adopt the “open” conformation seen in CaM-kinase complexes having increased calcium affinity. Most reports suggest TFP also increases calcium affinity of CaM. To compare TFP binding to apo CaM and (Ca2+)4-CaM, and explore differential effects on the N- and C-domains of CaM, stoichiometric TFP titrations of CaM were monitored by 15N-HSQC NMR. Two TFP bound to apo CaM, while four bound to (Ca2+)4-CaM. In both cases, the preferred site was in the C-domain. During the titrations, biphasic responses for some resonances suggested inter-site interactions. TFP-binding sites in apo CaM appeared distinct from those in (Ca2+)4-CaM. In equilibrium calcium titrations at defined ratios of TFP:CaM, TFP reduced calcium affinity at most levels tested; this is similar to the effect of many IQ-motifs on CaM. However, at the highest level tested, TFP raised the calcium affinity of the N-domain of CaM. A model of conformational switching is proposed to explain how TFP can exert opposing allosteric effects on calcium affinity by binding to different sites in the “closed”, “semi-open” and “open” domains of CaM. In physiological processes, apo CaM, as well as (Ca2+)4-CaM, needs to be considered a potential target of drug action.
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影响因子：
2.8
作者：
Liu, Yong;Buck, David C.;Neve, Kim A.
通讯作者：
Neve, Kim A.
影响因子：
7.3
作者：
Koevesi, Istvan;Menyhard, Dora K.;Fidy, Judit
通讯作者：
Fidy, Judit
影响因子：
5.7
作者：
Ataman, Zeynep Akyol;Gakhar, Lokesh;Shea, Madeline A.
通讯作者：
Shea, Madeline A.
影响因子：
2.7
作者：
DELAGLIO, F;GRZESIEK, S;BAX, A
通讯作者：
BAX, A
DOI：
10.1038/nsb0995-768
发表时间：
1995-09-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
KUBONIWA, H;TJANDRA, N;BAX, A
通讯作者：
BAX, A