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

Cell Res. 2016 May;26(5):574-92. doi: 10.1038/cr.2016.36. Epub 2016 Mar 22.


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 Ca(2+)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 Ca(2+)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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation
  • Amines / chemistry
  • Amino Acid Sequence
  • Amino Acids / genetics
  • Binding Sites
  • Calcium / metabolism
  • HEK293 Cells
  • Humans
  • Mutation / genetics
  • Pharmaceutical Preparations / chemistry*
  • Pharmaceutical Preparations / metabolism*
  • Receptors, Calcium-Sensing / chemistry*
  • Receptors, Calcium-Sensing / genetics
  • Receptors, Calcium-Sensing / metabolism*
  • Signal Transduction
  • Structure-Activity Relationship


  • Amines
  • Amino Acids
  • Pharmaceutical Preparations
  • Receptors, Calcium-Sensing
  • Calcium