[English] 日本語
Yorodumi Papers
- Database of articles cited by EMDB/PDB/SASBDB data -

+
Search query

Keywords
Structure methods
Author
Journal
IF

-
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

+
About Yorodumi Papers

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi Papers

Database of articles cited by EMDB/PDB/SASBDB data

  • Database of articles cited by EMDB, PDB, and SASBDB entries
  • Using PubMed data

Related info.:EMDB / PDB / SASBDB / Yorodumi / EMN Papers / Changes in new EM Navigator and Yorodumi

Read more