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- EMDB-28950: Structure of the leucine-rich repeat kinase 1 monomer -

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ID or keywords:

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Basic information

Entry
Database: EMDB / ID: EMD-28950
TitleStructure of the leucine-rich repeat kinase 1 monomer
Map dataComposite map used for refinement
Sample
  • Complex: Leucine-rich repeat kinase 1
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 1
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
Keywordskinase / LRRK / multi-domain protein / GTPase / TRANSFERASE
Function / homology
Function and homology information


negative regulation of peptidyl-tyrosine phosphorylation / osteoclast development / positive regulation of intracellular signal transduction / bone resorption / positive regulation of canonical Wnt signaling pathway / positive regulation of peptidyl-tyrosine phosphorylation / non-specific serine/threonine protein kinase / intracellular signal transduction / phosphorylation / protein serine kinase activity ...negative regulation of peptidyl-tyrosine phosphorylation / osteoclast development / positive regulation of intracellular signal transduction / bone resorption / positive regulation of canonical Wnt signaling pathway / positive regulation of peptidyl-tyrosine phosphorylation / non-specific serine/threonine protein kinase / intracellular signal transduction / phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / GTP binding / mitochondrion / ATP binding / identical protein binding / metal ion binding / cytosol
Similarity search - Function
C-terminal of Roc (COR) domain / C-terminal of Roc, COR, domain / Ras of Complex, Roc, domain of DAPkinase / Roc domain profile. / Roc domain / Leucine-rich repeats, bacterial type / Leucine Rich Repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. ...C-terminal of Roc (COR) domain / C-terminal of Roc, COR, domain / Ras of Complex, Roc, domain of DAPkinase / Roc domain profile. / Roc domain / Leucine-rich repeats, bacterial type / Leucine Rich Repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / WD40-repeat-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Leucine-rich repeat serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.92 Å
AuthorsMetcalfe RD / Martinez Fiesco JA / Zhang P
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)ZIA BC 011744 United States
CitationJournal: Nat Commun / Year: 2023
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
DepositionNov 25, 2022-
Header (metadata) releaseAug 16, 2023-
Map releaseAug 16, 2023-
UpdateAug 16, 2023-
Current statusAug 16, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28950.png

Downloads & links

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Map

FileDownload / File: emd_28950.map.gz / Format: CCP4 / Size: 307.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationComposite map used for refinement
Voxel sizeX=Y=Z: 0.81 Å
Density
Contour LevelBy AUTHOR: 7.0
Minimum - Maximum-44.854675 - 74.27543
Average (Standard dev.)-0.0025694945 (±0.9569201)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions432432432
Spacing432432432
CellA=B=C: 349.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Leucine-rich repeat kinase 1

EntireName: Leucine-rich repeat kinase 1
Components
  • Complex: Leucine-rich repeat kinase 1
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 1
  • Ligand: GUANOSINE-5'-DIPHOSPHATE

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Supramolecule #1: Leucine-rich repeat kinase 1

SupramoleculeName: Leucine-rich repeat kinase 1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 230 KDa

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Macromolecule #1: Leucine-rich repeat serine/threonine-protein kinase 1

MacromoleculeName: 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
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 229.556359 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: 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

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Macromolecule #2: GUANOSINE-5'-DIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-DIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 1 / Formula: GDP
Molecular weightTheoretical: 443.201 Da
Chemical component information

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM / Guanosine diphosphate

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.2 mg/mL
BufferpH: 8.3
VitrificationCryogen name: ETHANE / Instrument: LEICA EM GP
DetailsPurified LRRK1

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Image recordingFilm 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
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3553719
Details: Particles picked using a Topaz model trained on an initial LRRK1 dataset.
Startup modelType of model: NONE / Details: Ab-initio model generated using Cryosparc.
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.92 Å / Resolution method: FSC 0.143 CUT-OFF
Details: Resolution given for map is the resolution of the global refinement map (D_1000269296). The resolution for the local refinement map was 3.94 (D_1000269298).
Number images used: 183273

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