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Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor
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Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor
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Journal Article
Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor
2016
Overview
Drugs that allosterically target the human calcium-sensing receptor （CaSR） have substantial therapeutic potential, but are currently limited. Given the absence of high-resolution structures of the CaSR, we combined mutagenesis with a novel analytical approach and molecular modeling to develop an ＂enriched＂ picture of structure-function requirements for interaction between CaZ＋o and allosteric modulators within the CaSR＇s 7 transmembrane （7TM） domain. An extended cavity that accommodates multiple binding sites for structurally diverse ligands was identified. Phenylalkylamines bind to a site that overlaps with a putative Ca2＋o-binding site and extends towards an extracellu- lar vestibule. In contrast, the structurally and pharmacologically distinct AC-265347 binds deeper within the 7TM domains. Furthermore, distinct amino acid networks were found to mediate cooperativity by different modulators. These findings may facilitate the rational design of aliosteric modulators with distinct and potentially pathway-biased pharmacological effects.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Biomedical and Life Sciences
/ Calcium
/ Humans
/ Original
/ Pharmaceutical Preparations - chemistry
/ Pharmaceutical Preparations - metabolism
/ Receptors, Calcium-Sensing - chemistry
/ Receptors, Calcium-Sensing - genetics
/ Receptors, Calcium-Sensing - metabolism
/ Structure-Activity Relationship
/ 人类
/ 受体
/ 敏感
/ 结构功能
/ 药物
/ 药理作用
/ 钙
/ 高分辨率
