|Entry||Database: EMDB / ID: EMD-20480|
|Title||Human TRPM2 bound to ADPR and calcium|
|Map data||human TRPM2 bound with ADPR and calcium, unsharpened map|
|Function / homology|
Function and homology information
cellular response to purine-containing compound / mono-ADP-D-ribose binding / manganese ion transmembrane transporter activity / zinc ion transmembrane transport / response to purine-containing compound / dendritic cell differentiation / ligand-gated calcium channel activity / cellular response to temperature stimulus / regulation of filopodium assembly / sodium channel activity ...cellular response to purine-containing compound / mono-ADP-D-ribose binding / manganese ion transmembrane transporter activity / zinc ion transmembrane transport / response to purine-containing compound / dendritic cell differentiation / ligand-gated calcium channel activity / cellular response to temperature stimulus / regulation of filopodium assembly / sodium channel activity / TRP channels / regulation of actin cytoskeleton reorganization / response to hydroperoxide / estrous cycle / calcium ion transmembrane import into cytosol / positive regulation of oxidative stress-induced neuron death / dendritic cell chemotaxis / temperature homeostasis / calcium-release channel activity / calcium ion import across plasma membrane / ficolin-1-rich granule membrane / tertiary granule membrane / cation transmembrane transport / calcium-mediated signaling using intracellular calcium source / positive regulation of insulin secretion / release of sequestered calcium ion into cytosol / specific granule membrane / cation channel activity / cellular response to calcium ion / calcium ion transmembrane transport / calcium channel activity / cellular response to hydrogen peroxide / cytoplasmic vesicle membrane / calcium ion transport / perikaryon / protein homotetramerization / response to heat / lysosomal membrane / lysosome / neuron projection / Neutrophil degranulation / calcium ion binding / plasma membrane => GO:0005886 / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily M member 2 / SLOG in TRPM / TRPM, SLOG domain / NUDIX hydrolase domain / Nudix hydrolase domain profile. / NUDIX hydrolase-like domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Transient receptor potential cation channel subfamily M member 2
Similarity search - Component
|Biological species||Homo sapiens (human)|
|Method||single particle reconstruction / cryo EM / Resolution: 3.7 Å|
|Authors||Du J / Lu W / Huang Y|
|Funding support|| United States, 1 items |
|Citation||Journal: Elife / Year: 2019|
Title: Ligand recognition and gating mechanism through three ligand-binding sites of human TRPM2 channel.
Authors: Yihe Huang / Becca Roth / Wei Lü / Juan Du /
Abstract: TRPM2 is critically involved in diverse physiological processes including core temperature sensing, apoptosis, and immune response. TRPM2's activation by Ca and ADP ribose (ADPR), an NAD-metabolite ...TRPM2 is critically involved in diverse physiological processes including core temperature sensing, apoptosis, and immune response. TRPM2's activation by Ca and ADP ribose (ADPR), an NAD-metabolite produced under oxidative stress and neurodegenerative conditions, suggests a role in neurological disorders. We provide a central concept between triple-site ligand binding and the channel gating of human TRPM2. We show consecutive structural rearrangements and channel activation of TRPM2 induced by binding of ADPR in two indispensable locations, and the binding of Ca in the transmembrane domain. The 8-Br-cADPR-an antagonist of cADPR-binds only to the MHR1/2 domain and inhibits TRPM2 by stabilizing the channel in an apo-like conformation. We conclude that MHR1/2 acts as a orthostatic ligand-binding site for TRPM2. The NUDT9-H domain binds to a second ADPR to assist channel activation in vertebrates, but not necessary in invertebrates. Our work provides insights into the gating mechanism of human TRPM2 and its pharmacology.
|Structure viewer||EM map: |
Downloads & links
|File||Download / File: emd_20480.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)|
|Annotation||human TRPM2 bound with ADPR and calcium, unsharpened map|
|Projections & slices|
Images are generated by Spider.
|Voxel size||X=Y=Z: 1.074 Å|
|Symmetry||Space group: 1|
CCP4 map header:
-Entire : human TRPM2
|Entire||Name: human TRPM2|
-Supramolecule #1: human TRPM2
|Supramolecule||Name: human TRPM2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1|
|Source (natural)||Organism: Homo sapiens (human)|
|Recombinant expression||Organism: Homo sapiens (human)|
-Macromolecule #1: Transient receptor potential cation channel subfamily M member 2
|Macromolecule||Name: Transient receptor potential cation channel subfamily M member 2|
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
|Source (natural)||Organism: Homo sapiens (human)|
|Molecular weight||Theoretical: 172.280062 KDa|
|Recombinant expression||Organism: Homo sapiens (human)|
|Sequence||String: GSGGRATMEP SALRKAGSEQ EEGFEGLPRR VTDLGMVSNL RRSNSSLFKS WRLQCPFGNN DKQESLSSWI PENIKKKECV YFVESSKLS DAGKVVCQCG YTHEQHLEEA TKPHTFQGTQ WDPKKHVQEM PTDAFGDIVF TGLSQKVKKY VRVSQDTPSS V IYHLMTQH ...String: |
GSGGRATMEP SALRKAGSEQ EEGFEGLPRR VTDLGMVSNL RRSNSSLFKS WRLQCPFGNN DKQESLSSWI PENIKKKECV YFVESSKLS DAGKVVCQCG YTHEQHLEEA TKPHTFQGTQ WDPKKHVQEM PTDAFGDIVF TGLSQKVKKY VRVSQDTPSS V IYHLMTQH WGLDVPNLLI SVTGGAKNFN MKPRLKSIFR RGLVKVAQTT GAWIITGGSH TGVMKQVGEA VRDFSLSSSY KE GELITIG VATWGTVHRR EGLIHPTGSF PAEYILDEDG QGNLTCLDSN HSHFILVDDG THGQYGVEIP LRTRLEKFIS EQT KERGGV AIKIPIVCVV LEGGPGTLHT IDNATTNGTP CVVVEGSGRV ADVIAQVANL PVSDITISLI QQKLSVFFQE MFET FTESR IVEWTKKIQD IVRRRQLLTV FREGKDGQQD VDVAILQALL KASRSQDHFG HENWDHQLKL AVAWNRVDIA RSEIF MDEW QWKPSDLHPT MTAALISNKP EFVKLFLENG VQLKEFVTWD TLLYLYENLD PSCLFHSKLQ KVLVEDPERP ACAPAA PRL QMHHVAQVLR ELLGDFTQPL YPRPRHNDRL RLLLPVPHVK LNVQGVSLRS LYKRSSGHVT FTMDPIRDLL IWAIVQN RR ELAGIIWAQS QDCIAAALAC SKILKELSKE EEDTDSSEEM LALAEEYEHR AIGVFTECYR KDEERAQKLL TRVSEAWG K TTCLQLALEA KDMKFVSHGG IQAFLTKVWW GQLSVDNGLW RVTLCMLAFP LLLTGLISFR EKRLQDVGTP AARARAFFT APVVVFHLNI LSYFAFLCLF AYVLMVDFQP VPSWCECAIY LWLFSLVCEE MRQLFYDPDE CGLMKKAALY FSDFWNKLDV GAILLFVAG LTCRLIPATL YPGRVILSLD FILFCLRLMH IFTISKTLGP KIIIVKRMMK DVFFFLFLLA VWVVSFGVAK Q AILIHNER RVDWLFRGAV YHSYLTIFGQ IPGYIDGVNF NPEHCSPNGT DPYKPKCPES DATQQRPAFP EWLTVLLLCL YL LFTNILL LNLLIAMFNY TFQQVQEHTD QIWKFQRHDL IEEYHGRPAA PPPFILLSHL QLFIKRVVLK TPAKRHKQLK NKL EKNEEA ALLSWEIYLK ENYLQNRQFQ QKQRPEQKIE DISNKVDAMV DLLDLDPLKR SGSMEQRLAS LEEQVAQTAQ ALHW IVRTL RASGFSSEAD VPTLASQKAA EEPDAEPGGR KKTEEPGDSY HVNARHLLYP NCPVTRFPVP NEKVPWETEF LIYDP PFYT AERKDAAAMD PMGDTLEPLS TIQYNVVDGL RDRRSFHGPY TVQAGLPLNP MGRTGLRGRG SLSCFGPNHT LYPMVT RWR RNEDGAICRK SIKKMLEVLV VKLPLSEHWA LPGGSREPGE MLPRKLKRIL RQEHWPSFEN LLKCGMEVYK GYMDDPR NT DNAWIETVAV SVHFQDQNDV ELNRLNSNLH ACDSGASIRW QVVDRRIPLY ANHKTLLQKA AAEFGAHYFE
-Macromolecule #2: ADENOSINE-5-DIPHOSPHORIBOSE
|Macromolecule||Name: ADENOSINE-5-DIPHOSPHORIBOSE / type: ligand / ID: 2 / Number of copies: 8 / Formula: APR|
|Molecular weight||Theoretical: 559.316 Da|
|Chemical component information|
-Macromolecule #3: CALCIUM ION
|Macromolecule||Name: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 4 / Formula: CA|
|Molecular weight||Theoretical: 40.078 Da|
|Processing||single particle reconstruction|
|Vitrification||Cryogen name: ETHANE|
|Microscope||FEI TITAN KRIOS|
|Electron beam||Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN|
|Electron optics||C2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm|
|Sample stage||Cooling holder cryogen: NITROGEN|
|Image recording||Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-40 / Average exposure time: 8.0 sec. / Average electron dose: 6.8 e/Å2|
Model: Titan Krios / Image courtesy: FEI Company
|CTF correction||Software - Name: Gctf|
|Startup model||Type of model: OTHER / Details: cryosparc|
|Initial angle assignment||Type: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3)|
|Final angle assignment||Type: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3)|
|Final reconstruction||Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3) / Number images used: 287184|
-Atomic model buiding 1
|Refinement||Space: REAL / Protocol: AB INITIO MODEL|
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