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- EMDB-40504: Cryo-EM structure of TRPM7 N1098Q mutant in GDN detergent in comp... -

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Basic information

Entry
Database: EMDB / ID: EMD-40504
TitleCryo-EM structure of TRPM7 N1098Q mutant in GDN detergent in complex with inhibitor NS8593 in closed state
Map dataCryo-EM structure of TRPM7 N1098Q mutant in GDN detergent in complex with inhibitor NS8593 in closed state
Sample
  • Complex: sample 1
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 7
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • 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: N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-benzimidazol-2-amine
  • Ligand: CALCIUM ION
  • Ligand: CHOLESTEROL
Keywordstransient receptor potential M family member 7 / TRP / channel / TRPM7 / TRP channels / membrane protein / magnesium channel / inhibitor / ligand / NS8593
Function / homology
Function and homology information


intracellular magnesium ion homeostasis / calcium-dependent cell-matrix adhesion / monoatomic cation homeostasis / varicosity / TRP channels / actomyosin structure organization / myosin binding / monoatomic cation transmembrane transport / necroptotic process / monoatomic cation channel activity ...intracellular magnesium ion homeostasis / calcium-dependent cell-matrix adhesion / monoatomic cation homeostasis / varicosity / TRP channels / actomyosin structure organization / myosin binding / monoatomic cation transmembrane transport / necroptotic process / monoatomic cation channel activity / ruffle / protein tetramerization / calcium channel activity / memory / synaptic vesicle membrane / calcium ion transport / kinase activity / actin binding / non-specific serine/threonine protein kinase / protein kinase activity / positive regulation of apoptotic process / 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 / : ...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 / Ion transport domain / Ion transport protein / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Transient receptor potential cation channel subfamily M member 7
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.91 Å
AuthorsNadezhdin KD / Neuberger A / Sobolevsky AI
Funding support United States, Germany, 5 items
OrganizationGrant numberCountry
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
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)R01 AR078814 United States
German Research Foundation (DFG)464295817 Germany
CitationJournal: Nat Commun / Year: 2023
Title: Structural mechanisms of TRPM7 activation and inhibition.
Authors: Kirill D Nadezhdin / Leonor Correia / Chamali Narangoda / Dhilon S Patel / Arthur Neuberger / Thomas Gudermann / Maria G Kurnikova / Vladimir Chubanov / Alexander I Sobolevsky /
Abstract: The transient receptor potential channel TRPM7 is a master regulator of the organismal balance of divalent cations that plays an essential role in embryonic development, immune responses, cell ...The transient receptor potential channel TRPM7 is a master regulator of the organismal balance of divalent cations that plays an essential role in embryonic development, immune responses, cell mobility, proliferation, and differentiation. TRPM7 is implicated in neuronal and cardiovascular disorders, tumor progression and has emerged as a new drug target. Here we use cryo-EM, functional analysis, and molecular dynamics simulations to uncover two distinct structural mechanisms of TRPM7 activation by a gain-of-function mutation and by the agonist naltriben, which show different conformational dynamics and domain involvement. We identify a binding site for highly potent and selective inhibitors and show that they act by stabilizing the TRPM7 closed state. The discovered structural mechanisms provide foundations for understanding the molecular basis of TRPM7 channelopathies and drug development.
History
DepositionApr 14, 2023-
Header (metadata) releaseMay 17, 2023-
Map releaseMay 17, 2023-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40504.png

Downloads & links

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Map

FileDownload / File: emd_40504.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of TRPM7 N1098Q mutant in GDN detergent in complex with inhibitor NS8593 in closed state
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.81 Å/pix.
x 300 pix.
= 243. Å		0.81 Å/pix.
x 300 pix.
= 243. Å		0.81 Å/pix.
x 300 pix.
= 243. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.81 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.154
Minimum - Maximum-1.051688 - 1.3318865
Average (Standard dev.)0.010884894 (±0.04198353)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 243.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map 1

Fileemd_40504_half_map_1.map
AnnotationHalf Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_40504_half_map_2.map
AnnotationHalf Map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : sample 1

EntireName: sample 1
Components
  • Complex: sample 1
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 7
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • 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: N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-benzimidazol-2-amine
  • Ligand: CALCIUM ION
  • Ligand: CHOLESTEROL

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Supramolecule #1: sample 1

SupramoleculeName: sample 1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 700 KDa

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Macromolecule #1: Transient receptor potential cation channel subfamily M member 7

MacromoleculeName: 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: 146.902891 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SQKSWIESTL TKRECVYIIP SSKDPHRCLP GCQICQQLVR CFCGRLVKQH ACFTASLAMK YSDVKLGEHF NQAIEEWSVE KHTEQSPTD AYGVINFQGG SHSYRAKYVR LSYDTKPEII LQLLLKEWQM ELPKLVISVH GGMQKFELHP RIKQLLGKGL I KAAVTTGA ...String:
SQKSWIESTL TKRECVYIIP SSKDPHRCLP GCQICQQLVR CFCGRLVKQH ACFTASLAMK YSDVKLGEHF NQAIEEWSVE KHTEQSPTD AYGVINFQGG SHSYRAKYVR LSYDTKPEII LQLLLKEWQM ELPKLVISVH GGMQKFELHP RIKQLLGKGL I KAAVTTGA WILTGGVNTG VAKHVGDALK EHASRSSRKI CTIGIAPWGV IENRNDLVGR DVVAPYQTLL NPLSKLNVLN NL HSHFILV DDGTVGKYGA EVRLRRELEK TINQQRIHAR IGQGVPVVAL IFEGGPNVIL TVLEYLQESP PVPVVVCEGT GRA ADLLAY IHKQTEEGGN LPDAAEPDII STIKKTFNFG QSEAVHLFQT MMECMKKKEL ITVFHIGSED HQDIDVAILT ALLK GTNAS AFDQLILTLA WDRVDIAKNH VFVYGQQWLV GSLEQAMLDA LVMDRVSFVK LLIENGVSMH KFLTIPRLEE LYNTK QGPT NPMLFHLIRD VKQGNLPPGY KITLIDIGLV IEYLMGGTYR CTYTRKRFRL IYNSLGGNNR RSGRNTSSST PQLRKS HET FGNRADKKEK MRHNHFIKTA QPYRPKMDAS MEEGKKKRTK DEIVDIDDPE TKRFPYPLNE LLIWACLMKR QVMARFL WQ HGEESMAKAL VACKIYRSMA YEAKQSDLVD DTSEELKQYS NDFGQLAVEL LEQSFRQDET MAMKLLTYEL KNWSNSTC L KLAVSSRLRP FVAHTCTQML LSDMWMGRLN MRKNSWYKVI LSILVPPAIL MLEYKTKAEM SHIPQSQDAH QMTMEDSEN NFHNITEEIP MEVFKEVKIL DSSDGKNEME IHIKSKKLPI TRKFYAFYHA PIVKFWFNTL AYLGFLMLYT FVVLVKMEQL PSVQEWIVI AYIFTYAIEK VREVFMSEAG KISQKIKVWF SDYFNVSDTI AIISFFVGFG LRFGAKWNYI NAYDNHVFVA G RLIYCLNI IFWYVRLLDF LAVNQQAGPY VMMIGKMVAN MFYIVVIMAL VLLSFGVPRK AILYPHEEPS WSLAKDIVFH PY WMIFGEV YAYEIDVCAN DSTLPTICGP GTWLTPFLQA VYLFVQYIIM VNLLIAFFNQ VYLQVKAISN IVWKYQRYHF IMA YHEKPV LPPPLIILSH IVSLFCCVCK RRKKDKTSDG PKLFLTEEDQ KKLHDFEEQC VEMYFDEKDD KFNSGSEERI RVTF ERVEQ MSIQIKEVGD RVNYIKRSLQ SLDSQIGHLQ DLSALTVDTL KTLTAQKASE ASKVHNEITR ELSISKHLAQ NLID

UniProtKB: 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

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Macromolecule #3: 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: 3 / 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 #4: N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-benzimidazol-2-amine

MacromoleculeName: N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-benzimidazol-2-amine
type: ligand / ID: 4 / Number of copies: 4 / Formula: 6RA
Molecular weightTheoretical: 263.337 Da
Chemical component information

ChemComp-6RA:
N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-benzimidazol-2-amine

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Macromolecule #5: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #6: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 6 / Number of copies: 4 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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

Concentration3 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMtris(hydroxymethyl)aminomethane
1.0 mMbeta-Mercaptoethanol
0.01 %glyco-diosgenin
0.3 mMNS8593
GridModel: C-flat-1.2/1.3 / Support film - Material: GOLD / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
Detailsmouse TRPM7

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 11520 pixel / Digitization - Dimensions - Height: 8184 pixel / Number grids imaged: 1 / Number real images: 7659 / Average exposure time: 2.6 sec. / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1380320
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.91 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 139500
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-8sia:
Cryo-EM structure of TRPM7 N1098Q mutant in GDN detergent in complex with inhibitor NS8593 in closed state

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