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Open data
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Basic information
Entry | ![]() | |||||||||
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Title | Structure of the leucine-rich repeat kinase 1 monomer | |||||||||
![]() | Composite map used for refinement | |||||||||
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![]() | kinase / LRRK / multi-domain protein / GTPase / TRANSFERASE | |||||||||
Function / homology | ![]() negative regulation of peptidyl-tyrosine phosphorylation / positive regulation of intracellular signal transduction / osteoclast development / bone resorption / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of canonical Wnt signaling pathway / non-specific serine/threonine protein kinase / intracellular signal transduction / phosphorylation / protein serine kinase activity ...negative regulation of peptidyl-tyrosine phosphorylation / positive regulation of intracellular signal transduction / osteoclast development / bone resorption / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of canonical Wnt signaling pathway / non-specific serine/threonine protein kinase / intracellular signal transduction / phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / GTP binding / mitochondrion / ATP binding / membrane / identical protein binding / metal ion binding / cytosol Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.92 Å | |||||||||
![]() | Metcalfe RD / Martinez Fiesco JA / Zhang P | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structure and regulation of full-length human leucine-rich repeat kinase 1. Authors: Riley D Metcalfe / Juliana A Martinez Fiesco / Luis Bonet-Ponce / Jillian H Kluss / Mark R Cookson / Ping Zhang / ![]() Abstract: The human leucine-rich repeat kinases (LRRKs), LRRK1 and LRRK2 are large and unusually complex multi-domain kinases, which regulate fundamental cellular processes and have been implicated in human ...The human leucine-rich repeat kinases (LRRKs), LRRK1 and LRRK2 are large and unusually complex multi-domain kinases, which regulate fundamental cellular processes and have been implicated in human disease. Structures of LRRK2 have recently been determined, but the structure and molecular mechanisms regulating the activity of the LRRK1 as well as differences in the regulation of LRRK1 and LRRK2 remain unclear. Here, we report a cryo-EM structure of the LRRK1 monomer and a lower-resolution cryo-EM map of the LRRK1 dimer. The monomer structure, in which the kinase is in an inactive conformation, reveals key interdomain interfaces that control kinase activity as we validate experimentally. Both the LRRK1 monomer and dimer are structurally distinct compared to LRRK2. Overall, our results provide structural insights into the activation of the human LRRKs, which advance our understanding of their physiological and pathological roles. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 277.6 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 13 KB 13 KB | Display Display | ![]() |
Images | ![]() | 99.7 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 458.5 KB | Display | ![]() |
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Full document | ![]() | 458.1 KB | Display | |
Data in XML | ![]() | 7.7 KB | Display | |
Data in CIF | ![]() | 8.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8facMC C: citing same article ( M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homology ![]() |
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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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Annotation | Composite map used for refinement | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.81 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
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Sample components
-Entire : Leucine-rich repeat kinase 1
Entire | Name: Leucine-rich repeat kinase 1 |
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Components |
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-Supramolecule #1: Leucine-rich repeat kinase 1
Supramolecule | Name: Leucine-rich repeat kinase 1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 230 KDa |
-Macromolecule #1: Leucine-rich repeat serine/threonine-protein kinase 1
Macromolecule | Name: Leucine-rich repeat serine/threonine-protein kinase 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 229.556359 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MDYKDHDGDY KDHDIDYKDD DDKLGLEVLF QGPMAGMSQR PPSMYWCVGP EESAVCPERA METLNGAGDT GGKPSTRGGD PAARSRRTE GIRAAYRRGD RGGARDLLEE ACDQCASQLE KGQLLSIPAA YGDLEMVRYL LSKRLVELPT EPTDDNPAVV A AYFGHTAV ...String: MDYKDHDGDY KDHDIDYKDD DDKLGLEVLF QGPMAGMSQR PPSMYWCVGP EESAVCPERA METLNGAGDT GGKPSTRGGD PAARSRRTE GIRAAYRRGD RGGARDLLEE ACDQCASQLE KGQLLSIPAA YGDLEMVRYL LSKRLVELPT EPTDDNPAVV A AYFGHTAV VQELLESLPG PCSPQRLLNW MLALACQRGH LGVVKLLVLT HGADPESYAV RKNEFPVIVR LPLYAAIKSG NE DIAIFLL RHGAYFCSYI LLDSPDPSKH LLRKYFIEAS PLPSSYPGKT ALRVKWSHLR LPWVDLDWLI DISCQITELD LSA NCLATL PSVIPWGLIN LRKLNLSDNH LGELPGVQSS DEIICSRLLE IDISSNKLSH LPPGFLHLSK LQKLTASKNC LEKL FEEEN ATNWIGLRKL QELDISDNKL TELPALFLHS FKSLNSLNVS RNNLKVFPDP WACPLKCCKA SRNALECLPD KMAVF WKNH LKDVDFSENA LKEVPLGLFQ LDALMFLRLQ GNQLAALPPQ EKWTCRQLKT LDLSRNQLGK NEDGLKTKRI AFFTTR GRQ RSGTEAASVL EFPAFLSESL EVLCLNDNHL DTVPPSVCLL KSLSELYLGN NPGLRELPPE LGQLGNLWQL DTEDLTI SN VPAEIQKEGP KAMLSYLRAQ LRKAEKCKLM KMIIVGPPRQ GKSTLLEILQ TGRAPQVVHG EATIRTTKWE LQRPAGSR A KVESVEFNVW DIGGPASMAT VNQCFFTDKA LYVVVWNLAL GEEAVANLQF WLLNIEAKAP NAVVLVVGTH LDLIEAKFR VERIATLRAY VLALCRSPSG SRATGFPDIT FKHLHEISCK SLEGQEGLRQ LIFHVTCSMK DVGSTIGCQR LAGRLIPRSY LSLQEAVLA EQQRRSRDDD VQYLTDRQLE QLVEQTPDND IKDYEDLQSA ISFLIETGTL LHFPDTSHGL RNLYFLDPIW L SECLQRIF NIKGSRSVAK NGVIRAEDLR MLLVGTGFTQ QTEEQYFQFL AKFEIALPVA NDSYLLPHLL PSKPGLDTHG MR HPTANTI QRVFKMSFVP VGFWQRFIAR MLISLAEMDL QLFENKKNTK SRNRKVTIYS FTGNQRNRCS TFRVKRNQTI YWQ EGLLVT FDGGYLSVES SDVNWKKKKS GGMKIVCQSE VRDFSAMAFI TDHVNSLIDQ WFPALTATES DGTPLMEQYV PCPV CETAW AQHTDPSEKS EDVQYFDMED CVLTAIERDF ISCPRHPDLP VPLQELVPEL FMTDFPARLF LENSKLEHSE DEGSV LGQG GSGTVIYRAR YQGQPVAVKR FHIKKFKNFA NVPADTMLRH LRATDAMKNF SEFRQEASML HALQHPCIVA LIGISI HPL CFALELAPLS SLNTVLSENA RDSSFIPLGH MLTQKIAYQI ASGLAYLHKK NIIFCDLKSD NILVWSLDVK EHINIKL SD YGISRQSFHE GALGVEGTPG YQAPEIRPRI VYDEKVDMFS YGMVLYELLS GQRPALGHHQ LQIAKKLSKG IRPVLGQP E EVQFRRLQAL MMECWDTKPE KRPLALSVVS QMKDPTFATF MYELCCGKQT AFFSSQGQEY TVVFWDGKEE SRNYTVVNT EKGLMEVQRM CCPGMKVSCQ LQVQRSLWTA TEDQKIYIYT LKGMCPLNTP QQALDTPAVV TCFLAVPVIK KNSYLVLAGL ADGLVAVFP VVRGTPKDSC SYLCSHTANR SKFSIADEDA RQNPYPVKAM EVVNSGSEVW YSNGPGLLVI DCASLEICRR L EPYMAPSM VTSVVCSSEG RGEEVVWCLD DKANSLVMYH STTYQLCARY FCGVPSPLRD MFPVRPLDTE PPAASHTANP KV PEGDSIA DVSIMYSEEL GTQILIHQES LTDYCSMSSY SSSPPRQAAR SPSSLPSSPA SSSSVPFSTD CEDSDMLHTP GAA SDRSEH DLTPMDGETF SQHLQAVKIL AVRDLIWVPR RGGDVIVIGL EKDSGAQRGR VIAVLKAREL TPHGVLVDAA VVAK DTVVC TFENENTEWC LAVWRGWGAR EFDIFYQSYE ELGRLEACTR KRR UniProtKB: Leucine-rich repeat serine/threonine-protein kinase 1 |
-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: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 0.2 mg/mL |
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Buffer | pH: 8.3 |
Vitrification | Cryogen name: ETHANE / Instrument: LEICA EM GP |
Details | Purified LRRK1 |
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Electron microscopy
Microscope | FEI TALOS ARCTICA |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 7 / Number real images: 18074 / Average exposure time: 2.5 sec. / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | ![]() Model: Talos Arctica / Image courtesy: FEI Company |