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- PDB-8si6: Cryo-EM structure of TRPM7 in MSP2N2 nanodisc in complex with ago... -

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Basic information

Entry
Database: PDB / ID: 8si6
TitleCryo-EM structure of TRPM7 in MSP2N2 nanodisc in complex with agonist naltriben in closed state
ComponentsTransient receptor potential cation channel subfamily M member 7
KeywordsMEMBRANE PROTEIN / transient receptor potential M family member 7 / TRP / channel / TRPM7 / TRP channels / magnesium channel / agonist / ligand / naltriben
Function / homology
Function and homology information


calcium-dependent cell-matrix adhesion / intracellular magnesium ion homeostasis / magnesium ion transmembrane transport / zinc ion transport / zinc ion transmembrane transporter activity / magnesium ion transmembrane transporter activity / TRP channels / actomyosin structure organization / myosin binding / necroptotic process ...calcium-dependent cell-matrix adhesion / intracellular magnesium ion homeostasis / magnesium ion transmembrane transport / zinc ion transport / zinc ion transmembrane transporter activity / magnesium ion transmembrane transporter activity / TRP channels / actomyosin structure organization / myosin binding / necroptotic process / ruffle / cytoplasmic vesicle membrane / calcium channel activity / calcium ion transport / kinase activity / actin binding / protein autophosphorylation / cytoplasmic vesicle / protein homotetramerization / non-specific serine/threonine protein kinase / protein kinase activity / protein serine kinase activity / protein serine/threonine kinase activity / ATP binding / metal ion binding / nucleus / 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 / TRPM2-like domain / Ion transport domain / Ion transport protein / Protein kinase-like domain superfamily
Similarity search - Domain/homology
CHOLESTEROL / Chem-DU0 / Chem-POV / Chem-ZY8 / Transient receptor potential cation channel subfamily M member 7
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.44 Å
AuthorsNadezhdin, K.D. / Neuberger, A. / Sobolevsky, A.I.
Funding support United States, Germany, 5items
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, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 17, 2023Provider: repository / Type: Initial release
Revision 1.1May 24, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Oct 16, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily M member 7
B: Transient receptor potential cation channel subfamily M member 7
C: Transient receptor potential cation channel subfamily M member 7
D: Transient receptor potential cation channel subfamily M member 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)632,39569
Polymers587,5564
Non-polymers44,84065
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Transient receptor potential cation channel subfamily M member 7 / Channel-kinase 1 / Long transient receptor potential channel 7 / LTrpC-7 / LTrpC7 / Transient ...Channel-kinase 1 / Long transient receptor potential channel 7 / LTrpC-7 / LTrpC7 / Transient receptor potential-phospholipase C-interacting kinase / TRP-PLIK


Mass: 146888.875 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Trpm7, Chak, Ltrpc7 / Production host: Homo sapiens (human)
References: UniProt: Q923J1, non-specific serine/threonine protein kinase

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Non-polymers , 5 types, 65 molecules

#2: Chemical...
ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC


Mass: 760.076 Da / Num. of mol.: 52 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#3: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H46O
#4: Chemical
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


Mass: 516.752 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C32H52O5
#5: Chemical
ChemComp-ZY8 / (4bS,8R,8aS,14bR)-7-(cyclopropylmethyl)-5,6,7,8,9,14b-hexahydro-8aH-4,8-methanobis[1]benzofuro[3,2-e:2',3'-g]isoquinoline-1,8a-diol


Mass: 415.481 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H25NO4 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: sample 1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.7 MDa / Experimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human) / Cell: Human embryonic kidney 293 / Plasmid: pEG BacMam
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
220 mMtris(hydroxymethyl)aminomethane1
31 mMbeta-Mercaptoethanol1
40.2 mM1-(1,2R-dioctanoylphosphatidyl)inositol-4,5-bisphosphate1
51 mMnaltriben1
SpecimenConc.: 2.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: mouse TRPM7
Specimen supportGrid type: C-flat-1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 2.5 sec. / Electron dose: 58 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 5738
Image scansWidth: 5760 / Height: 4092

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Processing

EM software
IDNameVersionCategory
1cryoSPARC3.3.2particle selection
9PHENIX1.18model refinement
13cryoSPARC3.3.23D reconstruction
CTF correctionType: NONE
Particle selectionNum. of particles selected: 1408817
3D reconstructionResolution: 2.44 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 96984 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00880188
ELECTRON MICROSCOPYf_angle_d0.959146144
ELECTRON MICROSCOPYf_dihedral_angle_d11.87831980
ELECTRON MICROSCOPYf_chiral_restr0.0545692
ELECTRON MICROSCOPYf_plane_restr0.00511228

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