+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-41982 | |||||||||
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Title | Cryo-EM structure of LRRK2 bound to type I inhibitor GNE-7915 | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Cryo-EM / Parkinson's disease / Kinase / LRRK2 / type I inhibitor / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex | |||||||||
Function / homology | Function and homology information GTP-dependent protein kinase activity / regulation of signal transduction / protein autophosphorylation / cell differentiation / non-specific serine/threonine protein kinase / protein phosphorylation / GTP binding / ATP binding / cytosol Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.8 Å | |||||||||
Authors | Zhu H / Sun J | |||||||||
Funding support | United States, 1 items
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Citation | Journal: Cell Discov / Year: 2024 Title: Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM. Authors: Hanwen Zhu / Patricia Hixson / Wen Ma / Ji Sun / Abstract: LRRK2 is one of the most promising drug targets for Parkinson's disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being ...LRRK2 is one of the most promising drug targets for Parkinson's disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being actively pursued due to the potential undesired effects of type I inhibitors. Currently, a robust method for LRRK2-inhibitor structure determination to guide structure-based drug discovery is lacking, and inhibition mechanisms of available compounds are also unclear. Here we present near-atomic-resolution structures of LRRK2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors, uncovering the structural basis of LRRK2 inhibition and conformational plasticity of the kinase domain with molecular dynamics (MD) simulations. Type I and II inhibitors bind to LRRK2 in active-like and inactive conformations, so LRRK2-inhibitor complexes further reveal general structural features associated with LRRK2 activation. Our study provides atomic details of LRRK2-inhibitor interactions and a framework for understanding LRRK2 activation and for rational drug design. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_41982.map.gz | 59.4 MB | EMDB map data format | |
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Header (meta data) | emd-41982-v30.xml emd-41982.xml | 15 KB 15 KB | Display Display | EMDB header |
Images | emd_41982.png | 33.8 KB | ||
Filedesc metadata | emd-41982.cif.gz | 6.1 KB | ||
Others | emd_41982_half_map_1.map.gz emd_41982_half_map_2.map.gz | 59.5 MB 59.5 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-41982 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-41982 | HTTPS FTP |
-Validation report
Summary document | emd_41982_validation.pdf.gz | 744.6 KB | Display | EMDB validaton report |
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Full document | emd_41982_full_validation.pdf.gz | 744.1 KB | Display | |
Data in XML | emd_41982_validation.xml.gz | 12.3 KB | Display | |
Data in CIF | emd_41982_validation.cif.gz | 14.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-41982 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-41982 | HTTPS FTP |
-Related structure data
Related structure data | 8u7hMC 8fo7C 8u7lC 8u8aC 8u8bC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_41982.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.4895 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_41982_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_41982_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : LRRK2-GNE-7915
Entire | Name: LRRK2-GNE-7915 |
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Components |
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-Supramolecule #1: LRRK2-GNE-7915
Supramolecule | Name: LRRK2-GNE-7915 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 137 kDa/nm |
-Macromolecule #1: non-specific serine/threonine protein kinase
Macromolecule | Name: non-specific serine/threonine protein kinase / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 136.843469 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: KKAVPYNRMK LMIVGNTGSG KTTLLQQLMK TKKSDLGMQS ATVGIDVKDW PIQIRDKRKR DLVLNVWDFA GREEFYSTHP HFMTQRALY LAVYDLSKGQ AEVDAMKPWL FNIKARASSS PVILVGTHLD VSDEKQRKAC MSKITKELLN KRGFPAIRDY H FVNATEES ...String: KKAVPYNRMK LMIVGNTGSG KTTLLQQLMK TKKSDLGMQS ATVGIDVKDW PIQIRDKRKR DLVLNVWDFA GREEFYSTHP HFMTQRALY LAVYDLSKGQ AEVDAMKPWL FNIKARASSS PVILVGTHLD VSDEKQRKAC MSKITKELLN KRGFPAIRDY H FVNATEES DALAKLRKTI INESLNFKIR DQLVVGQLIP DCYVELEKII LSERKNVPIE FPVIDRKRLL QLVRENQLQL DE NELPHAV HFLNESGVLL HFQDPALQLS DLYFVEPKWL CKIMAQILTV KVEGCPKHPK GIISRRDVEK FLSKKRKFPK NYM TQYFKL LEKFQIALPI GEEYLLVPSS LSDHRPVIEL PHCENSEIII RLYEMPYFPM GFWSRLINRL LEISPYMLSG RERA LRPNR RYWRQGIYLN WSPEAYCLVG SEVLDNHPES FLKITVPSCR KGCILLGQVV DHIDSLMEEW FPGLLEIDIC GEGET LLKK WALYSFNDGE EHQKILLDDL MKKAEEGDLL VNPDQPRLTI PISQIAPDLI LADLPRNIML NNDELEFEQA PEFLLG DGS FGSVYRAAYE GEEVAVKIFN KHTSLRLLRQ ELVVLCHLHH PSLISLLAAG IRPRMLVMEL ASKGSLDRLL QQDKASL TR TLQHRIALHV ADGLRYLHSA MIIYRDLKPH NVLLFTLYPN AAIIAKIADY GIAQYCCRMG IKTSEGTPGF RAPEVARG N VIYNQQADVY SFGLLLYDIL TTGGRIVEGL KFPNEFDELE IQGKLPDPVK EYGCAPWPMV EKLIKQCLKE NPQERPTSA QVFDILNSAE LVCLTRRILL PKNVIVECMV ATHHNSRNAS IWLGCGHTDR GQLSFLDLNT EGYTSEEVAD SRILCLALVH LPVEKESWI VSGTQSGTLL VINTEDGKKR HTLEKMTDSV TCLYCNSFSK QSKQKNFLLV GTADGKLAIF EDKTVKLKGA A PLKILNIG NVSTPLMCLS ESTNSTERNV MWGGCGTKIF SFSNDFTIQK LIETRTSQLF SYAAFSDSNI ITVVVDTALY IA KQNSPVV EVWDKKTEKL CGLIDCVHFL REVTVKENKE SKHKTSYSGR VKTLCLQKNT ALWIGTGGGH ILLLDLSTRR LIR VIYNFC NSVRVMMTAQ LGSLKNVMLV LGYNRKNTEG TQKQKEIQSC LTVWDINLPH EVQNLEKHIE VRKELAEKMR RTSV E UniProtKB: non-specific serine/threonine protein kinase |
-Macromolecule #2: GUANOSINE-5'-DIPHOSPHATE
Macromolecule | Name: GUANOSINE-5'-DIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 1 / Formula: GDP |
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Molecular weight | Theoretical: 443.201 Da |
Chemical component information | ChemComp-GDP: |
-Macromolecule #3: [4-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-2-fl...
Macromolecule | Name: [4-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-2-fluoranyl-5-methoxy-phenyl]-morpholin-4-yl-methanone type: ligand / ID: 3 / Number of copies: 1 / Formula: A0T |
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Molecular weight | Theoretical: 443.395 Da |
Chemical component information | ChemComp-A0T: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 62.08 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 95644 |
Initial angle assignment | Type: OTHER |
Final angle assignment | Type: OTHER |