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- EMDB-43751: TRPM7 structure in complex with anticancer agent CCT128930 in clo... -

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Basic information

Entry
Database: EMDB / ID: EMD-43751
TitleTRPM7 structure in complex with anticancer agent CCT128930 in closed state
Map data
Sample
  • Complex: Complex of TRPM7 with antagonist CCT128930
    • Protein or peptide: Green fluorescent protein,Transient receptor potential cation channel subfamily M member 7
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: CHOLESTEROL
  • Ligand: 4-(4-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-aminium
  • Ligand: 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
  • Ligand: CALCIUM IONCalcium
  • Ligand: water
Keywordstransient receptor potential M family member 7 / TRP / channel / TRPM7 / TRP channels / membrane protein / CCT128930
Function / homology
Function and homology information


intracellular magnesium ion homeostasis / calcium-dependent cell-matrix adhesion / varicosity / TRP channels / actomyosin structure organization / myosin binding / monoatomic cation transmembrane transport / necroptotic process / monoatomic cation channel activity / ruffle ...intracellular magnesium ion homeostasis / calcium-dependent cell-matrix adhesion / varicosity / TRP channels / actomyosin structure organization / myosin binding / monoatomic cation transmembrane transport / necroptotic process / monoatomic cation channel activity / ruffle / bioluminescence / generation of precursor metabolites and energy / protein tetramerization / calcium channel activity / memory / synaptic vesicle membrane / calcium ion transport / actin binding / kinase activity / non-specific serine/threonine protein kinase / protein kinase activity / positive regulation of apoptotic process / phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / neuronal cell body / ATP binding / metal ion binding / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily M member 7 / MHCK/EF2 kinase / Alpha-kinase family / Alpha-type protein kinase domain profile. / Alpha-kinase family / TRPM, tetramerisation domain / TRPM, tetramerisation domain superfamily / Tetramerisation domain of TRPM / TRPM, SLOG domain / SLOG in TRPM ...Transient receptor potential cation channel subfamily M member 7 / MHCK/EF2 kinase / Alpha-kinase family / Alpha-type protein kinase domain profile. / Alpha-kinase family / TRPM, tetramerisation domain / TRPM, tetramerisation domain superfamily / Tetramerisation domain of TRPM / TRPM, SLOG domain / SLOG in TRPM / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / Ion transport domain / Ion transport protein / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Green fluorescent protein / Transient receptor potential cation channel subfamily M member 7
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.45 Å
AuthorsNadezhdin KD / Sobolevsky AI
Funding support United States, Germany, 5 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)R01 AR078814 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA206573 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01 NS083660 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01 NS107253 United States
German Research Foundation (DFG)464295817 Germany
CitationJournal: Cell Rep / Year: 2024
Title: Structural basis of selective TRPM7 inhibition by the anticancer agent CCT128930.
Authors: Kirill D Nadezhdin / Leonor Correia / Alexey Shalygin / Muhammed Aktolun / Arthur Neuberger / Thomas Gudermann / Maria G Kurnikova / Vladimir Chubanov / Alexander I Sobolevsky /
Abstract: 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 ...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.
History
DepositionFeb 20, 2024-
Header (metadata) releaseApr 17, 2024-
Map releaseApr 17, 2024-
UpdateApr 24, 2024-
Current statusApr 24, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43751.png

Downloads & links

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Map

FileDownload / File: emd_43751.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 320 pix.
= 320. Å		1 Å/pix.
x 320 pix.
= 320. Å		1 Å/pix.
x 320 pix.
= 320. Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.343
Minimum - Maximum-2.7935925 - 4.342617
Average (Standard dev.)0.0004104416 (±0.10416989)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 320.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_43751_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_43751_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of TRPM7 with antagonist CCT128930

EntireName: Complex of TRPM7 with antagonist CCT128930
Components
  • Complex: Complex of TRPM7 with antagonist CCT128930
    • Protein or peptide: Green fluorescent protein,Transient receptor potential cation channel subfamily M member 7
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: CHOLESTEROL
  • Ligand: 4-(4-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-aminium
  • Ligand: 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
  • Ligand: CALCIUM IONCalcium
  • Ligand: water

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Supramolecule #1: Complex of TRPM7 with antagonist CCT128930

SupramoleculeName: Complex of TRPM7 with antagonist CCT128930 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Molecular weightTheoretical: 700 KDa

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Macromolecule #1: Green fluorescent protein,Transient receptor potential cation cha...

MacromoleculeName: Green fluorescent protein,Transient receptor potential cation channel subfamily M member 7
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 175.75625 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MWSHPQFEKV SKGEELFTGV VPILVELDGD VNGHKFSVSG EGEGDATYGK LTLKFICTTG KLPVPWPTLV TTLTYGVQCF SRYPDHMKQ HDFFKSAMPE GYVQERTIFF KDDGNYKTRA EVKFEGDTLV NRIELKGIDF KEDGNILGHK LEYNYNSHNV Y IMADKQKN ...String:
MWSHPQFEKV SKGEELFTGV VPILVELDGD VNGHKFSVSG EGEGDATYGK LTLKFICTTG KLPVPWPTLV TTLTYGVQCF SRYPDHMKQ HDFFKSAMPE GYVQERTIFF KDDGNYKTRA EVKFEGDTLV NRIELKGIDF KEDGNILGHK LEYNYNSHNV Y IMADKQKN GIKVNFKIRH NIEDGSVQLA DHYQQNTPIG DGPVLLPDNH YLSTQSKLSK DPNEKRDHMV LLEFVTAAGI TL GMDELYK VDLVPRGSAQ KSWIESTLTK RECVYIIPSS KDPHRCLPGC QICQQLVRCF CGRLVKQHAC FTASLAMKYS DVK LGEHFN QAIEEWSVEK HTEQSPTDAY GVINFQGGSH SYRAKYVRLS YDTKPEIILQ LLLKEWQMEL PKLVISVHGG MQKF ELHPR IKQLLGKGLI KAAVTTGAWI LTGGVNTGVA KHVGDALKEH ASRSSRKICT IGIAPWGVIE NRNDLVGRDV VAPYQ TLLN PLSKLNVLNN LHSHFILVDD GTVGKYGAEV RLRRELEKTI NQQRIHARIG QGVPVVALIF EGGPNVILTV LEYLQE SPP VPVVVCEGTG RAADLLAYIH KQTEEGGNLP DAAEPDIIST IKKTFNFGQS EAVHLFQTMM ECMKKKELIT VFHIGSE DH QDIDVAILTA LLKGTNASAF DQLILTLAWD RVDIAKNHVF VYGQQWLVGS LEQAMLDALV MDRVSFVKLL IENGVSMH K FLTIPRLEEL YNTKQGPTNP MLFHLIRDVK QGNLPPGYKI TLIDIGLVIE YLMGGTYRCT YTRKRFRLIY NSLGGNNRR SGRNTSSSTP QLRKSHETFG NRADKKEKMR HNHFIKTAQP YRPKMDASME EGKKKRTKDE IVDIDDPETK RFPYPLNELL IWACLMKRQ VMARFLWQHG EESMAKALVA CKIYRSMAYE AKQSDLVDDT SEELKQYSND FGQLAVELLE QSFRQDETMA M KLLTYELK NWSNSTCLKL AVSSRLRPFV AHTCTQMLLS DMWMGRLNMR KNSWYKVILS ILVPPAILML EYKTKAEMSH IP QSQDAHQ MTMEDSENNF HNITEEIPME VFKEVKILDS SDGKNEMEIH IKSKKLPITR KFYAFYHAPI VKFWFNTLAY LGF LMLYTF VVLVKMEQLP SVQEWIVIAY IFTYAIEKVR EVFMSEAGKI SQKIKVWFSD YFNVSDTIAI ISFFVGFGLR FGAK WNYIN AYDNHVFVAG RLIYCLNIIF WYVRLLDFLA VNQQAGPYVM MIGKMVANMF YIVVIMALVL LSFGVPRKAI LYPHE EPSW SLAKDIVFHP YWMIFGEVYA YEIDVCANDS TLPTICGPGT WLTPFLQAVY LFVQYIIMVN LLIAFFNNVY LQVKAI SNI VWKYQRYHFI MAYHEKPVLP PPLIILSHIV SLFCCVCKRR KKDKTSDGPK LFLTEEDQKK LHDFEEQCVE MYFDEKD DK FNSGSEERIR VTFERVEQMS IQIKEVGDRV NYIKRSLQSL DSQIGHLQDL SALTVDTLKT LTAQKASEAS KVHNEITR E LSISKHLAQN LID

UniProtKB: Green fluorescent protein, Transient receptor potential cation channel subfamily M member 7

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Macromolecule #2: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 2 / Number of copies: 52 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

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

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 4 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Macromolecule #4: 4-(4-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4...

MacromoleculeName: 4-(4-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-aminium
type: ligand / ID: 4 / Number of copies: 4 / Formula: M05
Molecular weightTheoretical: 342.846 Da
Chemical component information

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

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Macromolecule #5: 2-[2-[(1~{S},2~{S},4~{S},5'~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13...

MacromoleculeName: 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
type: ligand / ID: 5 / Number of copies: 4 / Formula: DU0
Molecular weightTheoretical: 516.752 Da
Chemical component information

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

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Macromolecule #6: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 6 / Number of copies: 1 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 164 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.9 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClSodium chloridesodium chloride
20.0 mMTris-HClTris
0.4 mMCCT128930
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Support film - Material: GOLD
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.75 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v4.4.1)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.45 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v4.4.1) / Number images used: 433041
FSC plot (resolution estimation)

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