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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-10903 | |||||||||
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Title | Human TRPC5 in complex with Pico145 (HC-608)![]() | |||||||||
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Function / homology | ![]() regulation of membrane hyperpolarization / phosphatidylserine exposure on apoptotic cell surface / negative regulation of dendrite morphogenesis / Role of second messengers in netrin-1 signaling / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() | |||||||||
Method | ![]() ![]() | |||||||||
![]() | Wright DJ / Johnson RM / Muench SP / Bon RS | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Human TRPC5 structures reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site. Authors: David J Wright / Katie J Simmons / Rachel M Johnson / David J Beech / Stephen P Muench / Robin S Bon / ![]() Abstract: TRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered clinical trials. However, fundamental and translational ...TRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered clinical trials. However, fundamental and translational studies require a better understanding of TRPC1/4/5 channel regulation by endogenous and exogenous factors. Although several potent and selective TRPC1/4/5 modulators have been reported, the paucity of mechanistic insights into their modes-of-action remains a barrier to the development of new chemical probes and drug candidates. Xanthine-based modulators include the most potent and selective TRPC1/4/5 inhibitors described to date, as well as TRPC5 activators. Our previous studies suggest that xanthines interact with a, so far, elusive pocket of TRPC1/4/5 channels that is essential to channel gating. Here we report the structure of a small-molecule-bound TRPC1/4/5 channel-human TRPC5 in complex with the xanthine Pico145-to 3.0 Å. We found that Pico145 binds to a conserved lipid binding site of TRPC5, where it displaces a bound phospholipid. Our findings explain the mode-of-action of xanthine-based TRPC1/4/5 modulators, and suggest a structural basis for TRPC1/4/5 modulation by endogenous factors such as (phospho)lipids and Zn ions. These studies lay the foundations for the structure-based design of new generations of TRPC1/4/5 modulators. | |||||||||
History |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 59.8 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 13.1 KB 13.1 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 9.1 KB | Display | ![]() |
Images | ![]() | 80.6 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6ysnMC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1.07 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : Homotetrameric TRPC5
Entire | Name: Homotetrameric TRPC5 |
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Components |
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-Supramolecule #1: Homotetrameric TRPC5
Supramolecule | Name: Homotetrameric TRPC5 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() ![]() ![]() |
Recombinant expression | Organism: ![]() ![]() |
-Macromolecule #1: Maltose/maltodextrin-binding periplasmic protein,Short transient ...
Macromolecule | Name: Maltose/maltodextrin-binding periplasmic protein,Short transient receptor potential channel 5 type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 130.760031 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW P LIAADGGY ...String: MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW P LIAADGGY AFKYENGKYD IKDVGVDNAG AKAGLTFLVD LIKNKHMNAD TDYSIAEAAF NKGETAMTIN GPWAWSNIDT SK VNYGVTV LPTFKGQPSK PFVGVLSAGI NAASPNKELA KEFLENYLLT DEGLEAVNKD KPLGAVALKS YEEELAKDPR IAA TMENAQ KGEIMPNIPQ MSAFWYAVRT AVINAASGLE VRQTVDEALK DAQTSSGLGV LFQGPMAQLY YKKVNYSPYR DRIP LQIVR AETELSAEEK AFLNAVEKGD YATVKQALQE AEIYYNVNIN CMDPLGRSAL LIAIENENLE IMELLLNHSV YVGDA LLYA IRKEVVGAVE LLLSYRRPSG EKQVPTLMMD TQFSEFTPDI TPIMLAAHTN NYEIIKLLVQ KRVTIPRPHQ IRCNCV ECV SSSEVDSLRH SRSRLNIYKA LASPSLIALS SEDPILTAFR LGWELKELSK VENEFKAEYE ELSQQCKLFA KDLLDQA RS SRELEIILNH RDDHSEELDP QKYHDLAKLK VAIKYHQKEF VAQPNCQQLL ATLWYDGFPG WRRKHWVVKL LTCMTIGF L FPMLSIAYLI SPRSNLGLFI KKPFIKFICH TASYLTFLFM LLLASQHIVR TDLHVQGPPP TVVEWMILPW VLGFIWGEI KEMWDGGFTE YIHDWWNLMD FAMNSLYLAT ISLKIMAYVK YNGSRPREEW EMWHPTLIAE ALFAISNILS SLRLISLFTA NSHLGPLQI SLGRMLLDIL KFLFIYCLVL LAFANGLNQL YFYYETRAID EPNNCKGIRC EKQNNAFSTL FETLQSLFWS V FGLLNLYV TNVKARHEFT EFVGATMFGT YNVISLVVLL NMLIAMMNNS YQLIADHADI EWKFARTKLW MSYFDEGGTL PP PFNIIPS PKSFLYLGNW FNNTFCPKRD PDGRRRRRNL RSFTERNADS LIQNQHYQEV IRNLVKRYVA AMIRNSKTHE GLT EENFKE LKQDISSFRY EVLDLLGNRK |
-Macromolecule #2: 7-[(4-chlorophenyl)methyl]-3-methyl-1-(3-oxidanylpropyl)-8-[3-(tr...
Macromolecule | Name: 7-[(4-chlorophenyl)methyl]-3-methyl-1-(3-oxidanylpropyl)-8-[3-(trifluoromethyloxy)phenoxy]purine-2,6-dione type: ligand / ID: 2 / Number of copies: 4 / Formula: PJQ |
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Molecular weight | Theoretical: 524.877 Da |
Chemical component information | ![]() ChemComp-PJQ: |
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Concentration | 2 mg/mL | |||||||||||||||
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Buffer | pH: 7.5 Component:
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Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE | |||||||||||||||
Vitrification | Cryogen name: ETHANE | |||||||||||||||
Details | Final sample in PMAL-C8 amphipol |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average exposure time: 10.0 sec. / Average electron dose: 75.0 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |