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Structure paper

TitleLarge library docking identifies positive allosteric modulators of the calcium-sensing receptor.
Journal, issue, pagesScience, Vol. 385, Issue 6715, Page eado1868, Year 2024
Publish dateSep 20, 2024
AuthorsFangyu Liu / Cheng-Guo Wu / Chia-Ling Tu / Isabella Glenn / Justin Meyerowitz / Anat Levit Kaplan / Jiankun Lyu / Zhiqiang Cheng / Olga O Tarkhanova / Yurii S Moroz / John J Irwin / Wenhan Chang / Brian K Shoichet / Georgios Skiniotis /
PubMed AbstractPositive allosteric modulator (PAM) drugs enhance the activation of the calcium-sensing receptor (CaSR) and suppress parathyroid hormone (PTH) secretion. Unfortunately, these hyperparathyroidism- ...Positive allosteric modulator (PAM) drugs enhance the activation of the calcium-sensing receptor (CaSR) and suppress parathyroid hormone (PTH) secretion. Unfortunately, these hyperparathyroidism-treating drugs can induce hypocalcemia and arrhythmias. Seeking improved modulators, we docked libraries of 2.7 million and 1.2 billion molecules against the CaSR structure. The billion-molecule docking found PAMs with a 2.7-fold higher hit rate than the million-molecule library, with hits up to 37-fold more potent. Structure-based optimization led to nanomolar leads. In ex vivo organ assays, one of these PAMs was 100-fold more potent than the standard of care, cinacalcet, and reduced serum PTH levels in mice without the hypocalcemia typical of CaSR drugs. As determined from cryo-electron microscopy structures, the PAMs identified here promote CaSR conformations that more closely resemble the activated state than those induced by the established drugs.
External linksScience / PubMed:39298584
MethodsEM (single particle)
Resolution2.6 - 3.5 Å
Structure data

45127

9c1p

EMDB-45127, PDB-9c1p:
Structure of Calcium-Sensing Receptor in complex with positive allosteric modulator '6218
Method: EM (single particle) / Resolution: 2.8 Å

45156

9c2f

EMDB-45156, PDB-9c2f:
Structure of Calcium-Sensing Receptor in complex with positive allosteric modulator '54149
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-45792: Constituent EM map: focused refinement of the Venus flytrap (VFT) and cysteine-rich (CRD) domains of the calcium-sensing receptor.
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-45795: Focused refinement of the Heptahelical transmembrane (7TM) domain of the calcium-sensing receptor
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-45804: Raw Consensus map of the Calcium-Sensing Receptor in complex with positive allosteric modulator '6218
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-45882: Raw Consensus map of the Calcium-Sensing Receptor in complex with positive allosteric modulator '54149
Method: EM (single particle) / Resolution: 2.75 Å

EMDB-45901: Focused refinement of the Heptahelical transmembrane (7TM) domain of the calcium-sensing receptor bound to positive modulator '54149
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-45902: Focused refinement of the Venus flytrap domain of the calcium-sensing receptor bound to positive modulator '54149
Method: EM (single particle) / Resolution: 2.6 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-CA:
Unknown entry

ChemComp-TRP:
TRYPTOPHAN

ChemComp-PO4:
PHOSPHATE ION

PDB-1atp:
2.2 angstrom refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MNATP and a peptide inhibitor

PDB-1atx:
THREE-DIMENSIONAL STRUCTURE OF THE NEUROTOXIN ATX IA FROM ANEMONIA SULCATA IN AQUEOUS SOLUTION DETERMINED BY NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / G-protein coupled receptor / calcium-sensing

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