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TitleStructural basis of selective TRPM7 inhibition by the anticancer agent CCT128930.
Journal, issue, pagesCell Rep, Vol. 43, Issue 4, Page 114108, Year 2024
Publish dateApr 12, 2024
AuthorsKirill D Nadezhdin / Leonor Correia / Alexey Shalygin / Muhammed Aktolun / Arthur Neuberger / Thomas Gudermann / Maria G Kurnikova / Vladimir Chubanov / Alexander I Sobolevsky /
PubMed AbstractTRP channels are implicated in various diseases, but high structural similarity between them makes selective pharmacological modulation challenging. Here, we study the molecular mechanism underlying ...TRP channels are implicated in various diseases, but high structural similarity between them makes selective pharmacological modulation challenging. Here, we study the molecular mechanism underlying specific inhibition of the TRPM7 channel, which is essential for cancer cell proliferation, by the anticancer agent CCT128930 (CCT). Using cryo-EM, functional analysis, and MD simulations, we show that CCT binds to a vanilloid-like (VL) site, stabilizing TRPM7 in the closed non-conducting state. Similar to other allosteric inhibitors of TRPM7, NS8593 and VER155008, binding of CCT is accompanied by displacement of a lipid that resides in the VL site in the apo condition. Moreover, we demonstrate the principal role of several residues in the VL site enabling CCT to inhibit TRPM7 without impacting the homologous TRPM6 channel. Hence, our results uncover the central role of the VL site for the selective interaction of TRPM7 with small molecules that can be explored in future drug design.
External linksCell Rep / PubMed:38615321
MethodsEM (single particle)
Resolution2.45 Å
Structure data

43751

8w2l

EMDB-43751, PDB-8w2l:
TRPM7 structure in complex with anticancer agent CCT128930 in closed state
Method: EM (single particle) / Resolution: 2.45 Å

Chemicals

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM / POPC

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-M05:
4-(4-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-aminium

ChemComp-DU0:
2-[2-[(1~{S},2~{S},4~{S},5'~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S})-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icos-18-ene-6,2'-oxane]-16-yl]oxyethyl]propane-1,3-diol

ChemComp-CA:
Unknown entry

ChemComp-HOH:
WATER / Water

Source
  • mus musculus (house mouse)
  • aequorea victoria (jellyfish)
KeywordsMEMBRANE PROTEIN / transient receptor potential M family member 7 / TRP / channel / TRPM7 / TRP channels / CCT128930

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