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TitleIdentification of a binding site for small molecule inhibitors targeting human TRPM4.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 833, Year 2025
Publish dateJan 19, 2025
AuthorsBabatunde Ekundayo / Prakash Arullampalam / Christian E Gerber / Anne-Flore Hämmerli / Sabrina Guichard / Mey Boukenna / Daniela Ross-Kaschitza / Martin Lochner / Jean-Sebastien Rougier / Henning Stahlberg / Hugues Abriel / Dongchun Ni /
PubMed AbstractTransient receptor potential (TRP) melastatin 4 (TRPM4) protein is a calcium-activated monovalent cation channel associated with various genetic and cardiovascular disorders. The anthranilic acid ...Transient receptor potential (TRP) melastatin 4 (TRPM4) protein is a calcium-activated monovalent cation channel associated with various genetic and cardiovascular disorders. The anthranilic acid derivative NBA is a potent and specific TRPM4 inhibitor, but its binding site in TRPM4 has been unknown, although this information is crucial for drug development targeting TRPM4. We determine three cryo-EM structures of full-length human TRPM4 embedded in native lipid nanodiscs without inhibitor, bound to NBA, and an anthranilic acid derivative, IBA. We found that the small molecules NBA and IBA were bound in a pocket formed between the S3, S4, and TRP helices and the S4-S5 linker of TRPM4. Our structural data and results from patch clamp experiments enable validation of a binding site for small molecule inhibitors, paving the way for further drug development targeting TRPM4.
External linksNat Commun / PubMed:39828793 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 4.4 Å
Structure data

19057

8rcr

EMDB-19057, PDB-8rcr:
human TRPM4 in SMA apo
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-19060: HTRPM4-NBA
Method: EM (single particle) / Resolution: 4.4 Å

19061

8rcu

EMDB-19061, PDB-8rcu:
human TRPM4 in SMA IBA
Method: EM (single particle) / Resolution: 3.5 Å

19069

8rd9

EMDB-19069, PDB-8rd9:
human TRPM4 in SMA NBA
Method: EM (single particle) / Resolution: 4.3 Å

EMDB-19072: DDM/CHS HTRPM4
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-19073: human TRPM4 LMNG ligand CA
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-19074: mouse TRPM4 with ligand DDM/CHS
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL

PDB-1hz5:
CRYSTAL STRUCTURES OF THE B1 DOMAIN OF PROTEIN L FROM PEPTOSTREPTOCOCCUS MAGNUS, WITH A TYROSINE TO TRYPTOPHAN SUBSTITUTION

PDB-1h0c:
The crystal structure of human alanine:glyoxylate aminotransferase

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / trpm / inhibitor

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