Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor

Katie Leach, Karen Gregory, Irina Kufareva, Elham Khajehali, Anna E Cook, Ruben Abagyan, Arthur D Conigrave, Patrick M Sexton, Arthur Christopoulos

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62 Citations (Scopus)


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 Ca2+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 extracellular 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 allosteric modulators with distinct and potentially pathway-biased pharmacological effects.

Original languageEnglish
Pages (from-to)574-592
Number of pages19
JournalCell Research
Issue number5
Publication statusPublished - 1 May 2016


  • allosteric modulation
  • drug discovery
  • G protein-coupled receptor
  • molecular modeling
  • mutagenesis
  • structural biology

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