Details of the Target

General Information of Target

Target ID LDTP07056
Target Name Leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2)
Gene Name LRRK2
Gene ID 120892
Synonyms
PARK8; Leucine-rich repeat serine/threonine-protein kinase 2; EC 2.7.11.1; EC 3.6.5.-; Dardarin
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Sequence
MASGSCQGCEEDEETLKKLIVRLNNVQEGKQIETLVQILEDLLVFTYSERASKLFQGKNI
HVPLLIVLDSYMRVASVQQVGWSLLCKLIEVCPGTMQSLMGPQDVGNDWEVLGVHQLILK
MLTVHNASVNLSVIGLKTLDLLLTSGKITLLILDEESDIFMLIFDAMHSFPANDEVQKLG
CKALHVLFERVSEEQLTEFVENKDYMILLSALTNFKDEEEIVLHVLHCLHSLAIPCNNVE
VLMSGNVRCYNIVVEAMKAFPMSERIQEVSCCLLHRLTLGNFFNILVLNEVHEFVVKAVQ
QYPENAALQISALSCLALLTETIFLNQDLEEKNENQENDDEGEEDKLFWLEACYKALTWH
RKNKHVQEAACWALNNLLMYQNSLHEKIGDEDGHFPAHREVMLSMLMHSSSKEVFQASAN
ALSTLLEQNVNFRKILLSKGIHLNVLELMQKHIHSPEVAESGCKMLNHLFEGSNTSLDIM
AAVVPKILTVMKRHETSLPVQLEALRAILHFIVPGMPEESREDTEFHHKLNMVKKQCFKN
DIHKLVLAALNRFIGNPGIQKCGLKVISSIVHFPDALEMLSLEGAMDSVLHTLQMYPDDQ
EIQCLGLSLIGYLITKKNVFIGTGHLLAKILVSSLYRFKDVAEIQTKGFQTILAILKLSA
SFSKLLVHHSFDLVIFHQMSSNIMEQKDQQFLNLCCKCFAKVAMDDYLKNVMLERACDQN
NSIMVECLLLLGADANQAKEGSSLICQVCEKESSPKLVELLLNSGSREQDVRKALTISIG
KGDSQIISLLLRRLALDVANNSICLGGFCIGKVEPSWLGPLFPDKTSNLRKQTNIASTLA
RMVIRYQMKSAVEEGTASGSDGNFSEDVLSKFDEWTFIPDSSMDSVFAQSDDLDSEGSEG
SFLVKKKSNSISVGEFYRDAVLQRCSPNLQRHSNSLGPIFDHEDLLKRKRKILSSDDSLR
SSKLQSHMRHSDSISSLASEREYITSLDLSANELRDIDALSQKCCISVHLEHLEKLELHQ
NALTSFPQQLCETLKSLTHLDLHSNKFTSFPSYLLKMSCIANLDVSRNDIGPSVVLDPTV
KCPTLKQFNLSYNQLSFVPENLTDVVEKLEQLILEGNKISGICSPLRLKELKILNLSKNH
ISSLSENFLEACPKVESFSARMNFLAAMPFLPPSMTILKLSQNKFSCIPEAILNLPHLRS
LDMSSNDIQYLPGPAHWKSLNLRELLFSHNQISILDLSEKAYLWSRVEKLHLSHNKLKEI
PPEIGCLENLTSLDVSYNLELRSFPNEMGKLSKIWDLPLDELHLNFDFKHIGCKAKDIIR
FLQQRLKKAVPYNRMKLMIVGNTGSGKTTLLQQLMKTKKSDLGMQSATVGIDVKDWPIQI
RDKRKRDLVLNVWDFAGREEFYSTHPHFMTQRALYLAVYDLSKGQAEVDAMKPWLFNIKA
RASSSPVILVGTHLDVSDEKQRKACMSKITKELLNKRGFPAIRDYHFVNATEESDALAKL
RKTIINESLNFKIRDQLVVGQLIPDCYVELEKIILSERKNVPIEFPVIDRKRLLQLVREN
QLQLDENELPHAVHFLNESGVLLHFQDPALQLSDLYFVEPKWLCKIMAQILTVKVEGCPK
HPKGIISRRDVEKFLSKKRKFPKNYMSQYFKLLEKFQIALPIGEEYLLVPSSLSDHRPVI
ELPHCENSEIIIRLYEMPYFPMGFWSRLINRLLEISPYMLSGRERALRPNRMYWRQGIYL
NWSPEAYCLVGSEVLDNHPESFLKITVPSCRKGCILLGQVVDHIDSLMEEWFPGLLEIDI
CGEGETLLKKWALYSFNDGEEHQKILLDDLMKKAEEGDLLVNPDQPRLTIPISQIAPDLI
LADLPRNIMLNNDELEFEQAPEFLLGDGSFGSVYRAAYEGEEVAVKIFNKHTSLRLLRQE
LVVLCHLHHPSLISLLAAGIRPRMLVMELASKGSLDRLLQQDKASLTRTLQHRIALHVAD
GLRYLHSAMIIYRDLKPHNVLLFTLYPNAAIIAKIADYGIAQYCCRMGIKTSEGTPGFRA
PEVARGNVIYNQQADVYSFGLLLYDILTTGGRIVEGLKFPNEFDELEIQGKLPDPVKEYG
CAPWPMVEKLIKQCLKENPQERPTSAQVFDILNSAELVCLTRRILLPKNVIVECMVATHH
NSRNASIWLGCGHTDRGQLSFLDLNTEGYTSEEVADSRILCLALVHLPVEKESWIVSGTQ
SGTLLVINTEDGKKRHTLEKMTDSVTCLYCNSFSKQSKQKNFLLVGTADGKLAIFEDKTV
KLKGAAPLKILNIGNVSTPLMCLSESTNSTERNVMWGGCGTKIFSFSNDFTIQKLIETRT
SQLFSYAAFSDSNIITVVVDTALYIAKQNSPVVEVWDKKTEKLCGLIDCVHFLREVMVKE
NKESKHKMSYSGRVKTLCLQKNTALWIGTGGGHILLLDLSTRRLIRVIYNFCNSVRVMMT
AQLGSLKNVMLVLGYNRKNTEGTQKQKEIQSCLTVWDINLPHEVQNLEKHIEVRKELAEK
MRRTSVE
Target Type
Clinical trial
Target Bioclass
Enzyme
Family
Protein kinase superfamily, TKL Ser/Thr protein kinase family
Subcellular location
Cytoplasmic vesicle
Function
Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, innate immunity, autophagy, and vesicle trafficking. Is a key regulator of RAB GTPases by regulating the GTP/GDP exchange and interaction partners of RABs through phosphorylation. Phosphorylates RAB3A, RAB3B, RAB3C, RAB3D, RAB5A, RAB5B, RAB5C, RAB8A, RAB8B, RAB10, RAB12, RAB35, and RAB43. Regulates the RAB3IP-catalyzed GDP/GTP exchange for RAB8A through the phosphorylation of 'Thr-72' on RAB8A. Inhibits the interaction between RAB8A and GDI1 and/or GDI2 by phosphorylating 'Thr-72' on RAB8A. Regulates primary ciliogenesis through phosphorylation of RAB8A and RAB10, which promotes SHH signaling in the brain. Together with RAB29, plays a role in the retrograde trafficking pathway for recycling proteins, such as mannose-6-phosphate receptor (M6PR), between lysosomes and the Golgi apparatus in a retromer-dependent manner. Regulates neuronal process morphology in the intact central nervous system (CNS). Plays a role in synaptic vesicle trafficking. Plays an important role in recruiting SEC16A to endoplasmic reticulum exit sites (ERES) and in regulating ER to Golgi vesicle-mediated transport and ERES organization. Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes. Phosphorylates PRDX3. By phosphorylating APP on 'Thr-743', which promotes the production and the nuclear translocation of the APP intracellular domain (AICD), regulates dopaminergic neuron apoptosis. Acts as a positive regulator of innate immunity by mediating phosphorylation of RIPK2 downstream of NOD1 and NOD2, thereby enhancing RIPK2 activation. Independent of its kinase activity, inhibits the proteasomal degradation of MAPT, thus promoting MAPT oligomerization and secretion. In addition, has GTPase activity via its Roc domain which regulates LRRK2 kinase activity.
TTD ID
T08123
Uniprot ID
Q5S007
DrugMap ID
TT1HI8U
Ensemble ID
ENST00000298910.12
HGNC ID
HGNC:18618
ChEMBL ID
CHEMBL1075104

Probe(s) Labeling This Target

ABPP Probe
Click To Hide/Show 2 Probe Related to This Target
Probe name Structure Binding Site(Ratio) Interaction ID Ref
BTD
 Probe Info  		C1618(1.22)  LDD2128  [1]
Phosphinate-6
 Probe Info  		N.A.  LDD0018  [2]

Competitor(s) Related to This Target

Competitor ID Name Cell line Binding Site(Ratio) Interaction ID Ref
 LDCM0535  Nucleophilic fragment 30b MDA-MB-231 C1618(1.22)  LDD2128  [1]

The Interaction Atlas With This Target

The Protein(s) Related To This Target

Enzyme
Click To Hide/Show 44 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
S-adenosylhomocysteine hydrolase-like protein 1 (AHCYL1) Adenosylhomocysteinase family O43865
Protein argonaute-2 (AGO2) Argonaute family Q9UKV8
Enoyl-CoA hydratase, mitochondrial (ECHS1) Enoyl-CoA hydratase/isomerase family P30084
Heat shock cognate 71 kDa protein (HSPA8) Heat shock protein 70 family P11142
Ribonuclease P protein subunit p25 (RPP25) Histone-like Alba family Q9BUL9
L-lactate dehydrogenase B chain (LDHB) LDH family P07195
Protein arginine methyltransferase NDUFAF7, mitochondrial (NDUFAF7) NDUFAF7 family Q7L592
Ubiquitin carboxyl-terminal hydrolase 39 (USP39) Peptidase C19 family Q53GS9
Thioredoxin-dependent peroxide reductase, mitochondrial (PRDX3) Peroxiredoxin family P30048
Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A) Phosphatase 2A regulatory subunit B family P63151
Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA) PPP phosphatase family P62136
cAMP-dependent protein kinase catalytic subunit alpha (PRKACA) AGC Ser/Thr protein kinase family P17612
RAC-alpha serine/threonine-protein kinase (AKT1) AGC Ser/Thr protein kinase family P31749
Death-associated protein kinase 1 (DAPK1) CAMK Ser/Thr protein kinase family P53355
Glycogen synthase kinase-3 beta (GSK3B) CMGC Ser/Thr protein kinase family P49841
Serine/threonine-protein kinase Nek1 (NEK1) NEK Ser/Thr protein kinase family Q96PY6
Cyclin-G-associated kinase (GAK) Ser/Thr protein kinase family O14976
Dual specificity mitogen-activated protein kinase kinase 3 (MAP2K3) STE Ser/Thr protein kinase family P46734
Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6) STE Ser/Thr protein kinase family P52564
Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7) STE Ser/Thr protein kinase family O14733
Serine/threonine-protein kinase PAK 6 (PAK6) STE Ser/Thr protein kinase family Q9NQU5
Leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2) TKL Ser/Thr protein kinase family Q5S007
Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1) TKL Ser/Thr protein kinase family Q38SD2
Megakaryocyte-associated tyrosine-protein kinase (MATK) Tyr protein kinase family P42679
E3 ubiquitin-protein ligase parkin (PRKN) RBR family, Parkin subfamily O60260
Ras-related protein Rab-10 (RAB10) Rab family P61026
Ras-related protein Rab-12 (RAB12) Rab family Q6IQ22
Ras-related protein Rab-1B (RAB1B) Rab family Q9H0U4
Ras-related protein Rab-32 (RAB32) Rab family Q13637
Ras-related protein Rab-38 (RAB38) Rab family P57729
Ras-related protein Rab-5B (RAB5B) Rab family P61020
Ras-related protein Rab-7L1 (RAB29) Rab family O14966
Ras-related protein Rab-8A (RAB8A) Rab family P61006
Ras-related C3 botulinum toxin substrate 1 (RAC1) Rho family P63000
Cell division control protein 42 homolog (CDC42) Rho family P60953
Dynamin-1 (DNM1) Dynamin/Fzo/YdjA family Q05193
Dynamin-1-like protein (DNM1L) Dynamin/Fzo/YdjA family O00429
Dynamin-like 120 kDa protein, mitochondrial (OPA1) Dynamin/Fzo/YdjA family O60313
Mitofusin-2 (MFN2) Dynamin/Fzo/YdjA family O95140
Elongation factor 1-alpha 2 (EEF1A2) Classic translation factor GTPase family Q05639
Small ribosomal subunit protein uS3 (RPS3) Universal ribosomal protein uS3 family P23396
Ankyrin repeat and SAM domain-containing protein 4B (ANKS4B) . Q8N8V4
E3 ubiquitin-protein ligase CBL-B (CBLB) . Q13191
E3 ubiquitin-protein ligase CHIP (STUB1) . Q9UNE7
Transporter and channel
Click To Hide/Show 13 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
14-3-3 protein epsilon (YWHAE) 14-3-3 family P62258
14-3-3 protein gamma (YWHAG) 14-3-3 family P61981
14-3-3 protein theta (YWHAQ) 14-3-3 family P27348
14-3-3 protein zeta/delta (YWHAZ) 14-3-3 family P63104
Hsp90 co-chaperone Cdc37 (CDC37) CDC37 family Q16543
Secretogranin-1 (CHGB) Chromogranin/secretogranin protein family P05060
Voltage-dependent anion-selective channel protein 1 (VDAC1) Eukaryotic mitochondrial porin family P21796
ADP/ATP translocase 1 (SLC25A4) Mitochondrial carrier (TC 2.A.29) family P12235
ADP/ATP translocase 2 (SLC25A5) Mitochondrial carrier (TC 2.A.29) family P05141
ADP/ATP translocase 3 (SLC25A6) Mitochondrial carrier (TC 2.A.29) family P12236
Nuclear pore complex protein Nup133 (NUP133) Nucleoporin Nup133 family Q8WUM0
SNARE-associated protein Snapin (SNAPIN) SNAPIN family O95295
Alpha-synuclein (SNCA) Synuclein family P37840
Transcription factor
Click To Hide/Show 2 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Ribosome quality control complex subunit TCF25 (TCF25) TCF25 family Q9BQ70
Nuclear factor of activated T-cells, cytoplasmic 2 (NFATC2) . Q13469
Other
Click To Hide/Show 50 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
14-3-3 protein beta/alpha (YWHAB) 14-3-3 family P31946
14-3-3 protein eta (YWHAH) 14-3-3 family Q04917
14-3-3 protein sigma (SFN) 14-3-3 family P31947
AP-3 complex subunit beta-1 (AP3B1) Adaptor complexes large subunit family O00203
Large ribosomal subunit protein bL19m (MRPL19) Bacterial ribosomal protein bL19 family P49406
Cdc42 effector protein 3 (CDC42EP3) BORG/CEP family Q9UKI2
Cilia- and flagella-associated protein 20 (CFAP20) CFAP20 family Q9Y6A4
Segment polarity protein dishevelled homolog DVL-2 (DVL2) DSH family O14641
Segment polarity protein dishevelled homolog DVL-3 (DVL3) DSH family Q92997
26S proteasome complex subunit SEM1 (SEM1) DSS1/SEM1 family P60896
Endophilin-A1 (SH3GL2) Endophilin family Q99962
Endophilin-A2 (SH3GL1) Endophilin family Q99961
Large ribosomal subunit protein eL13 (RPL13) Eukaryotic ribosomal protein eL13 family P26373
Large ribosomal subunit protein eL14 (RPL14) Eukaryotic ribosomal protein eL14 family P50914
Large ribosomal subunit protein eL30 (RPL30) Eukaryotic ribosomal protein eL30 family P62888
Large ribosomal subunit protein eL34 (RPL34) Eukaryotic ribosomal protein eL34 family P49207
Small ribosomal subunit protein eS27 (RPS27) Eukaryotic ribosomal protein eS27 family P42677
La-related protein 7 (LARP7) LARP7 family Q4G0J3
Low-density lipoprotein receptor-related protein 6 (LRP6) LDLR family O75581
Protein transport protein Sec16A (SEC16A) SEC16 family O15027
Tetratricopeptide repeat protein 27 (TTC27) TTC27 family Q6P3X3
Tubulin beta chain (TUBB) Tubulin family P07437
Tubulin beta-2A chain (TUBB2A) Tubulin family Q13885
Tubulin beta-4A chain (TUBB4A) Tubulin family P04350
Tubulin beta-4B chain (TUBB4B) Tubulin family P68371
Tubulin beta-6 chain (TUBB6) Tubulin family Q9BUF5
Large ribosomal subunit protein uL1 (RPL10A) Universal ribosomal protein uL1 family P62906
Large ribosomal subunit protein uL23 (RPL23A) Universal ribosomal protein uL23 family P62750
Small ribosomal subunit protein uS10 (RPS20) Universal ribosomal protein uS10 family P60866
Small ribosomal subunit protein uS12 (RPS23) Universal ribosomal protein uS12 family P62266
Small ribosomal subunit protein uS13 (RPS18) Universal ribosomal protein uS13 family P62269
Small ribosomal subunit protein uS15 (RPS13) Universal ribosomal protein uS15 family P62277
Small ribosomal subunit protein uS17 (RPS11) Universal ribosomal protein uS17 family P62280
Small ribosomal subunit protein uS19 (RPS15) Universal ribosomal protein uS19 family P62841
Small ribosomal subunit protein uS5 (RPS2) Universal ribosomal protein uS5 family P15880
Small ribosomal subunit protein uS9 (RPS16) Universal ribosomal protein uS9 family P62249
Zinc finger Ran-binding domain-containing protein 2 (ZRANB2) ZRANB2 family O95218
BAG family molecular chaperone regulator 2 (BAG2) . O95816
BAG family molecular chaperone regulator 3 (BAG3) . O95817
BAG family molecular chaperone regulator 5 (BAG5) . Q9UL15
CUE domain-containing protein 1 (CUEDC1) . Q9NWM3
FAS-associated death domain protein (FADD) . Q13158
La-related protein 4 (LARP4) . Q71RC2
Moesin (MSN) . P26038
Nuclear inhibitor of protein phosphatase 1 (PPP1R8) . Q12972
Regulator of G-protein signaling 2 (RGS2) . P41220
Rho guanine nucleotide exchange factor 7 (ARHGEF7) . Q14155
Sequestosome-1 (SQSTM1) . Q13501
Spermatogenesis-associated protein 22 (SPATA22) . Q8NHS9
WD repeat and SOCS box-containing protein 1 (WSB1) . Q9Y6I7

The Drug(s) Related To This Target

Approved
Click To Hide/Show 1 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
Fostamatinib Small molecular drug DB12010
Patented
Click To Hide/Show 1 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
Fused Thiophene Derivative 1 Small molecular drug D0FS9X

References

1 Nucleophilic covalent ligand discovery for the cysteine redoxome. Nat Chem Biol. 2023 Nov;19(11):1309-1319. doi: 10.1038/s41589-023-01330-5. Epub 2023 May 29.
Mass spectrometry data entry: PXD039908 , PXD029761
2 DFT-Guided Discovery of Ethynyl-Triazolyl-Phosphinates as Modular Electrophiles for Chemoselective Cysteine Bioconjugation and Profiling. Angew Chem Int Ed Engl. 2022 Oct 10;61(41):e202205348. doi: 10.1002/anie.202205348. Epub 2022 Aug 22.
Mass spectrometry data entry: PXD033004