Structural determinants of natriuretic peptide receptor specificity and degeneracy
Structural determinants of natriuretic peptide receptor specificity and degeneracy
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DOI：
10.1016/j.jmb.2006.06.060
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发表时间：
2006-08-25
影响因子：
5.6
通讯作者：
Garcia, K. Christopher
中科院分区：
文献类型：
--
作者：
He, Xiao-lin;Dukkipati, Abhiram;Garcia, K. Christopher
心血管稳态和血压调节部分依赖于利钠肽（NP）激素和利钠肽受体（NPR）之间的相互作用。C型NPR（NPR-C）负责从循环中清除NP激素，并显示出与所有NP激素（ANP、BNP和CNP）的交叉反应性，而其他NPR的特异性更受限制。为了阐明NPR-C与NP激素的结合特异性和交叉反应性的结构决定因素，我们已经确定了NPR-C与心房利钠肽（ANP）和脑利钠肽（BNP）的复合物的晶体结构。这些复合物的结构比较，与以前的NPR-C/CNP复合物的结构，揭示了NPR-C使用构象不灵活的表面结合三种不同的，高度灵活的，NP配体。复杂的结构支持刚性混杂的机制，而不是通过受体的构象可塑性。虽然ANP和BNP似乎采用相似的受体结合构象，但CNP结构不同，但与其他配体共享一组共同的受体接触。不同NPR的退化与选择性激素识别特性似乎主要来自受体表面上的两个腔，口袋I和口袋II，其作为激素侧链的锚定位点并调节受体选择性。(c)2006爱思唯尔有限公司保留所有权利。
Cardiovascular homeostasis and blood pressure regulation are reliant, in part, on interactions between natriuretic peptide (NP) hormones and natriuretic peptide receptors (NPR). The C-type NPR (NPR-C) is responsible for clearance of NP hormones from the circulation, and displays a cross-reactivity for all NP hormones (ANP, BNP, and CNP), in contrast to other NPRs, which are more restricted in their specificity. In order to elucidate the structural determinants for the binding specificity and cross-reactivity of NPR-C with NP hormones, we have determined the crystal structures of the complexes of NPR-C with atrial natriuretic peptide (ANP), and with brain natriuretic peptide (BNP). A structural comparison of these complexes, with the previous structure of the NPR-C/CNP complex, reveals that NPR-C uses a conformationally inflexible surface to bind three different, highly flexible, NP ligands. The complex structures support a mechanism of rigid promiscuity rather than conformational plasticity by the receptor. While ANP and BNP appear to adopt similar receptor-bound conformations, the CNP structure diverges, yet shares sets of common receptor contacts with the other ligands. The degenerate versus selective hormone recognition properties of different NPRs appears to derive largely from two cavities on the receptor surfaces, pocket I and pocket II, that serve as anchoring sites for hormone side-chains and modulate receptor selectivity. (c) 2006 Elsevier Ltd. All rights reserved.