[English] 日本語
Yorodumi
- PDB-8w2l: TRPM7 structure in complex with anticancer agent CCT128930 in clo... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 8w2l
TitleTRPM7 structure in complex with anticancer agent CCT128930 in closed state
ComponentsGreen fluorescent protein,Transient receptor potential cation channel subfamily M member 7
KeywordsMEMBRANE PROTEIN / transient receptor potential M family member 7 / TRP / channel / TRPM7 / TRP channels / CCT128930
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 / bioluminescence / generation of precursor metabolites and energy / calcium channel activity / calcium ion transport / kinase activity / protein autophosphorylation / actin binding / 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 / 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
CHOLESTEROL / Chem-DU0 / Chem-M05 / Chem-POV / Green fluorescent protein / Transient receptor potential cation channel subfamily M member 7
Similarity search - Component
Biological speciesAequorea victoria (jellyfish)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.45 Å
AuthorsNadezhdin, K.D. / Sobolevsky, A.I.
Funding support United States, Germany, 5items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 17, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 13, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

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


Theoretical massNumber of molelcules
Total (without water)747,57469
Polymers703,0254
Non-polymers44,54965
Water2,954164
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

-
Components

-
Protein , 1 types, 4 molecules ABCD

#1: Protein
Green fluorescent protein,Transient receptor potential cation channel subfamily M member 7


Mass: 175756.250 Da / Num. of mol.: 4 / Fragment: residues 3-1280 of the TRPM7 channel
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Aequorea victoria (jellyfish), (gene. exp.) Mus musculus (house mouse)
Gene: GFP, Trpm7, Chak, Ltrpc7 / Production host: Homo sapiens (human)
References: UniProt: P42212, UniProt: Q923J1, non-specific serine/threonine protein kinase

-
Non-polymers , 6 types, 229 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-M05 / 4-(4-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-aminium


Mass: 342.846 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H21ClN5 / Feature type: SUBJECT OF INVESTIGATION
#5: 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
#6: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 164 / Source method: isolated from a natural source / Formula: H2O

-
Details

Has ligand of interestY
Has protein modificationY

-
Experimental details

-
Experiment

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

-
Sample preparation

ComponentName: Complex of TRPM7 with antagonist CCT128930 / Type: COMPLEX / Entity ID: #1 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.7 MDa / Experimental value: NO
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
220 mMTris-HCl1
30.4 mMCCT1289301
SpecimenConc.: 1.9 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE

-
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: 750 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

-
Processing

EM software
IDNameVersionCategory
4cryoSPARCv4.4.1CTF correction
10cryoSPARCv4.4.1final Euler assignment
11cryoSPARCv4.4.1classification
12cryoSPARCv4.4.13D reconstruction
13PHENIX1.18model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.45 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 433041 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00674000
ELECTRON MICROSCOPYf_angle_d0.998134884
ELECTRON MICROSCOPYf_dihedral_angle_d12.92929484
ELECTRON MICROSCOPYf_chiral_restr0.0535232
ELECTRON MICROSCOPYf_plane_restr0.00910276

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more