[English] 日本語
Yorodumi
- PDB-9c76: LRRK2 Roc domain RP (Ras-pocket) complexed to Divarasib -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 9c76
TitleLRRK2 Roc domain RP (Ras-pocket) complexed to Divarasib
ComponentsLeucine-rich repeat serine/threonine-protein kinase 2
KeywordsSIGNALING PROTEIN / GTPase / Complex / chemical biology / switch II
Function / homology
Function and homology information


caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / regulation of kidney size / regulation of neuron maturation / regulation of cell projection organization / tangential migration from the subventricular zone to the olfactory bulb ...caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / regulation of kidney size / regulation of neuron maturation / regulation of cell projection organization / tangential migration from the subventricular zone to the olfactory bulb / protein localization to endoplasmic reticulum exit site / GTP-dependent protein kinase activity / regulation of neuroblast proliferation / regulation of ER to Golgi vesicle-mediated transport / peroxidase inhibitor activity / negative regulation of late endosome to lysosome transport / regulation of mitochondrial depolarization / negative regulation of protein targeting to mitochondrion / positive regulation of dopamine receptor signaling pathway / regulation of synaptic vesicle transport / regulation of CAMKK-AMPK signaling cascade / regulation of lysosomal lumen pH / amphisome / co-receptor binding / mitochondrion localization / negative regulation of excitatory postsynaptic potential / regulation of retrograde transport, endosome to Golgi / regulation of dopamine receptor signaling pathway / positive regulation of microglial cell activation / positive regulation of synaptic vesicle endocytosis / negative regulation of autophagosome assembly / cytoplasmic side of mitochondrial outer membrane / neuron projection arborization / regulation of cAMP/PKA signal transduction / olfactory bulb development / striatum development / multivesicular body, internal vesicle / regulation of dendritic spine morphogenesis / protein localization to mitochondrion / JUN kinase kinase kinase activity / cellular response to dopamine / endoplasmic reticulum organization / positive regulation of protein autoubiquitination / Wnt signalosome / positive regulation of programmed cell death / negative regulation of protein processing / GTP metabolic process / syntaxin-1 binding / regulation of canonical Wnt signaling pathway / negative regulation of GTPase activity / exploration behavior / regulation of reactive oxygen species metabolic process / lysosome organization / clathrin binding / Golgi-associated vesicle / regulation of locomotion / protein kinase A binding / phosphorylation / negative regulation of macroautophagy / PTK6 promotes HIF1A stabilization / neuromuscular junction development / regulation of synaptic vesicle exocytosis / regulation of mitochondrial fission / Golgi organization / intracellular distribution of mitochondria / locomotory exploration behavior / regulation of synaptic vesicle endocytosis / endoplasmic reticulum exit site / autolysosome / microvillus / MAP kinase kinase kinase activity / negative regulation of Notch signaling pathway / positive regulation of protein kinase activity / Rho protein signal transduction / cellular response to manganese ion / canonical Wnt signaling pathway / presynaptic cytosol / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / regulation of synaptic transmission, glutamatergic / phagocytic vesicle / JNK cascade / positive regulation of autophagy / dendrite cytoplasm / negative regulation of protein binding / peptidyl-threonine phosphorylation / positive regulation of MAP kinase activity / tubulin binding / GTPase activator activity / SNARE binding / neuron projection morphogenesis / cellular response to starvation / positive regulation of protein ubiquitination / regulation of membrane potential / excitatory postsynaptic potential / determination of adult lifespan / cellular response to reactive oxygen species / mitochondrion organization / trans-Golgi network / calcium-mediated signaling / mitochondrial membrane
Similarity search - Function
LRRK2 ARM repeat / LRRK2 ANK repeat / LRRK2 beta propeller / : / C-terminal of Roc (COR) domain / C-terminal of Roc, COR-A domain / Ras of Complex, Roc, domain of DAPkinase / Roc domain profile. / Roc domain / Leucine-rich repeats, bacterial type ...LRRK2 ARM repeat / LRRK2 ANK repeat / LRRK2 beta propeller / : / C-terminal of Roc (COR) domain / C-terminal of Roc, COR-A 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 / Rab subfamily of small GTPases / Leucine-rich repeat domain superfamily / Ankyrin repeat-containing domain superfamily / Armadillo-like helical / Small GTP-binding protein domain / Armadillo-type fold / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / WD40-repeat-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / BROMIDE ION / FLUORIDE ION / GUANOSINE-5'-DIPHOSPHATE / IODIDE ION / Leucine-rich repeat serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsZhu, L.Y. / Guiley, K.Z. / Shokat, K.M.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)F31NS122434 United States
Michael J. Fox Foundation17461 United States
CitationJournal: To Be Published
Title: LRRK2 Roc domain RP (Ras-pocket) complexed to Divarasib
Authors: Zhu, L.Y. / Shokat, K.M.
History
DepositionJun 10, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2024Group: Structure summary / Category: audit_author / Item: _audit_author.name

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Leucine-rich repeat serine/threonine-protein kinase 2
B: Leucine-rich repeat serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,47613
Polymers42,9082
Non-polymers2,56911
Water1,72996
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.411, 98.379, 105.203
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 3 through 29 or (resid 41...
d_2ens_1(chain "B" and (resid 3 through 24 or (resid 25...
d_1ens_2chain "C"
d_2ens_2chain "D"
d_1ens_3chain "G"
d_2ens_3chain "H"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1VALVALLYSLYSAA3 - 293 - 29
d_12ens_1THRTHRARGARGAA41 - 18741 - 187
d_21ens_1VALVALLYSLYSBB3 - 293 - 29
d_22ens_1THRTHRGLYGLYBB41 - 9741 - 97
d_23ens_1GLUGLUVALVALBB100 - 129100 - 129
d_24ens_1GLUGLUTHRTHRBB132 - 143132 - 143
d_25ens_1LEULEULEULEUBB146 - 147146 - 147
d_26ens_1PROPROARGARGBB153 - 187153 - 187
d_11ens_2GDPGDPGDPGDPCC1
d_21ens_2GDPGDPGDPGDPDD1
d_11ens_3LRJLRJLRJLRJGL1
d_21ens_3LRJLRJLRJLRJHM1

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(0.465516363205, 0.881275749353, 0.0815326265386), (0.877988912895, -0.471449110277, 0.082892733413), (0.111489839995, 0.0329968183455, -0.993217612388)4.30014974406, -4.5823768633, -22.2398627674
2given(0.432032194611, 0.888980504899, 0.151861268037), (0.87545780057, -0.453841115009, 0.166138140561), (0.216614455291, 0.0611711062321, -0.97433889049)4.38083380262, -3.75553967892, -20.7865631355
3given(0.534059721438, 0.825320637191, 0.183374097855), (0.836240762657, -0.483748603221, -0.258241506644), (-0.124425081108, 0.291261282544, -0.948517403363)4.54514299617, -9.56938874326, -17.2827201949

-
Components

-
Protein , 1 types, 2 molecules AB

#1: Protein Leucine-rich repeat serine/threonine-protein kinase 2 / Dardarin


Mass: 21453.811 Da / Num. of mol.: 2 / Fragment: Roc domain
Mutation: N1342A, T1343C, P1433H, W1434Y, N1437Q, K1460A, K1463A, C1465A (Uniprot numbering)
Source method: isolated from a genetically manipulated source
Details: N-His-TEV protein, cleaved / Source: (gene. exp.) Homo sapiens (human) / Gene: LRRK2, PARK8 / Production host: Escherichia coli (E. coli)
References: UniProt: Q5S007, non-specific serine/threonine protein kinase, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement

-
Non-polymers , 7 types, 107 molecules

#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-BR / BROMIDE ION


Mass: 79.904 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Br
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-F / FLUORIDE ION


Mass: 18.998 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: F
#6: Chemical ChemComp-A1AWR / 1-{(3S)-4-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-3-methylpiperazin-1-yl}propan-1-one / divarasib, bound form


Mass: 624.073 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H34ClF4N7O2 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: I
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 96 / Source method: isolated from a natural source / Formula: H2O

-
Details

Has ligand of interestY
Has protein modificationY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 2.41 Å3/Da / Density % sol: 48.9 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: Morpheus Fusion C7: 30 mM Halides 0.12 M Monosaccharide 1 0.1 M Buffer System 1 pH 6.5 30% Precipitant mix 1

-
Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 2.0.1 / Wavelength: 1.02808 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 13, 2023
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.02808 Å / Relative weight: 1
ReflectionResolution: 2.3→49.19 Å / Num. obs: 19323 / % possible obs: 99.8 % / Redundancy: 6.2 % / CC1/2: 0.978 / Rpim(I) all: 0.129 / Rrim(I) all: 0.332 / Net I/σ(I): 9.9
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 6.4 % / Mean I/σ(I) obs: 2.4 / Num. unique obs: 1866 / CC1/2: 0.715 / % possible all: 99.7

-
Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→35.22 Å / SU ML: 0.3217 / Cross valid method: FREE R-VALUE / Phase error: 28.163
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2668 1935 10.04 %
Rwork0.2268 17332 -
obs0.231 19267 99.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 53.74 Å2
Refinement stepCycle: LAST / Resolution: 2.3→35.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2644 0 149 96 2889
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00512843
X-RAY DIFFRACTIONf_angle_d0.80973863
X-RAY DIFFRACTIONf_chiral_restr0.0495439
X-RAY DIFFRACTIONf_plane_restr0.0089470
X-RAY DIFFRACTIONf_dihedral_angle_d17.13881029
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS2.37059230065
ens_2d_2CAX-RAY DIFFRACTIONTorsion NCS0.401307939839
ens_3d_2MBX-RAY DIFFRACTIONTorsion NCS1.49614063499
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.360.33291250.29111235X-RAY DIFFRACTION99.56
2.36-2.420.33381540.26941164X-RAY DIFFRACTION99.85
2.42-2.490.30781360.28611225X-RAY DIFFRACTION99.71
2.49-2.570.30921190.26351237X-RAY DIFFRACTION99.93
2.57-2.660.36581500.27911220X-RAY DIFFRACTION99.85
2.66-2.770.30061240.28611229X-RAY DIFFRACTION99.71
2.77-2.90.30171430.25271236X-RAY DIFFRACTION99.71
2.9-3.050.30041320.26351217X-RAY DIFFRACTION99.78
3.05-3.240.34581450.24811218X-RAY DIFFRACTION99.85
3.24-3.490.27491330.23641249X-RAY DIFFRACTION99.86
3.49-3.840.25461360.20391242X-RAY DIFFRACTION99.78
3.84-4.40.2241420.19061265X-RAY DIFFRACTION99.58
4.4-5.530.21351440.18071274X-RAY DIFFRACTION99.65
5.54-35.220.23771520.22011321X-RAY DIFFRACTION98.07

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more