The active state of the AT(1) angiotensin receptor is generated by angiotensin II induction
The active state of the AT(1) angiotensin receptor is generated by angiotensin II induction
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DOI：
10.1021/bi961593m
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发表时间：
1996-12-24
期刊：
影响因子：
2.9
通讯作者：
Karnik, SS
中科院分区：
文献类型：
--
作者：
Noda, K;Feng, YH;Karnik, SS
在目前的受体激活模型中，给定的激素不参与将非活性受体(R)转换为完全活性状态(R*)。相反，它优先选择激活的受体构象，从而使平衡朝着R*方向移动。血管紧张素II(Ang II)含有两个残基，Tyr(4)和Phe(8)，它们是兴奋所必需的。我们发现AT(1)血管紧张素受体跨膜螺旋UT中保守的ASN(111)直接与Tyr(4)侧链相互作用。ASN(111)侧链尺寸的减小诱导中间激活的受体构象(R‘)。Ang II类似物[Sar(1)，Ile(4)，Ile(8)]Ang II完全激活N111G突变体，表明从R‘到R*的转变或R*状态的稳定需要Ang II结合，但不需要它的Tyr(4)和Phe(8)侧链结合。相反，[Sar(1)，Ile(4)，Ile(8)]Ang II结合但不激活野生型AT(1)受体(R)，这表明在野生型受体中R‘和R*状态的自发出现是罕见的。因此，Ang II通过涉及Tyr(4)和Phe(8)的相互作用诱导从R‘到R’的转变，并且通过未指定的相互作用诱导从R‘到R*状态的转变，而不是通过’构象选择‘来稳定自发产生的R*态。
In the current model of receptor activation, the given hormone is not involved in the conversion of the inactive receptor (R) to the fully active state (R*). Rather, it preferentially selects the activated receptor conformation, thereby shifting the equilibrium toward R*. The hormone angiotensin II (Ang II) contains two residues, Tyr(4) and Phe(8), that are essential for agonism. We show that the conserved Asn(111) in transmembrane helix UT of the AT(1) angiotensin receptor directly interacts with the Tyr(4) side chain. A decrease in the size of the Asn(111) side chain induces an intermediate activated receptor conformation (R'). The Ang II analogue [Sar(1),Ile(4),Ile(8)]Ang II, fully activates the N111G mutant, indicating that either the transition from R' to R* or the stabilization of the R* state requires binding by Ang II but not its Tyr(4) and Phe(8) side chains. In contrast, [Sar(1),Ile(4),Ile(8)]Ang II binds to but does not activate the wild-type AT(1) receptor (R), suggesting that in the wild-type receptor spontaneous occurrence of R' and R* states is rare. Thus, Ang II through interactions involving Tyr(4) and Phe(8) induces a transition from R to R' and through unspecified interactions induces transition from R' to R* states rather than stabilizing the spontaneously generated R* state by ''conformational selection''.