Structure of PDB 8u8a Chain C Binding Site BS01

Receptor Information
>8u8a Chain C (length=1705) Species: 9606 (Homo sapiens) [Search protein sequence] [Download receptor structure] [Download structure with residue number starting from 1] [View receptor structure]
GIQKCGLKVISSIVHFPDALGAMDSVLHTLQMYPDDQEIQCLGLSLIGYT
GHLLAKILVSSLYRFKDVAEIQTKGFQTILAILKLSASFSKLLVHHSFDL
VIFHQMSSNIMEQKDQQFLNLCCKCFAKVAMDDYLKNVMLERACDQNNSI
MVECLLLLGADANQASSLICQVCEKESSPKLVELLLNSGSREQDVRKALT
ISIGKGDSQIISLLLRRLALDVANNSICLGGFCIGKVEPSWLGPLFPDKT
SNLRKQTNIASTLARMVIRYQMKSAVEREYITSLDLSANELRDIDALSQK
CCISVHLEHLEKLELHQNALTSFPQQLCETLKSLTHLDLHSNKFTSFPSY
LLKMSCIANLDVSRNDIGPSVVLDPTVKCPTLKQFNLSYNQLSFVPENLT
DVVEKLEQLILEGNKISGICSPLRLKELKILNLSKNHISSLSENFLEACP
KVESFSARMNFLAAMPFLPPSMTILKLSQNKFSCIPEAILNLPHLRSLDM
SSNDIQYLPGPAHWKSLNLRELLFSHNQISILDLSEKAYLWSRVEKLHLS
HNKLKEIPPEIGCLENLTSLDVSYNLELRSFPNEMGKLSKIWDLPLDELH
LNFDFKHIGCKAKDIIRFLQQRLKKAVPYNRMKLMIVGNTGSGKTTLLQQ
LMKTKSATVGIDVKDWPIQIRDKRKRDLVLNVWDFAGREEFYSTHPHFMT
QRALYLAVYDLSKGQAEVDAMKPWLFNIKARASSSPVILVGTHLDVSKAC
MSKITKELLNKRGFPAIRDYHFVNATEESDALAKLRKTIINESLNFKIRD
QLVVGQLIPDCYVELEKIILSERKNVPIEFPVIDRKRLLQLVRENQLQLD
ENELPHAVHFLNESGVLLHFQDPALQLSDLYFVEPKWLCKIMAQILTVPK
NYMTQYFKLLEKFQIALVPSSLSDHRPVIELPHCENSEIIIRLYEMPYFP
MGFWSRLINRLLEISPYMLALRPNRMYWRQGIYLNWSPEAYCLVGSEVLD
NHPESFLKITVPSCRKGCILLGQVVDHIDSLMEEWFPGLLEIDGETLLKK
WALYSFNDGEEHQKILLDDLMKKAEEGDLLVNPDQPRLTIPISQIAPDLI
LADLPRNIMLNNDELEFEQAPEFLLGDGSFGSVYRAAYEGEEVAVKIFNK
HTSLRLLRQELVVLCHLHHPSLISLLAAGIRPRMLVMELASKGSLDRLLQ
QDKASLTRTLQHRIALHVADGLRYLHSAMIIYRDLKPHNVLLFTLYPNAA
IIAKIADYGIGTPGFRAPEVARGNVIYNQQADVYSFGLLLYDILTTGGRI
VKLPDPVKEYGCAPWPMVEKLIKQCLKENPQERPTSAQVFDILNSAELVC
LTRRILLPKNVIVECMVATHHNSRNASIWLGCGHTDRGQLSFLDLNTEGY
TSEEVADSRILCLALVHLPVEKESWIVSGTQSGTLLVINTEDGKKRHTLE
KMTDSVTCLYCNSNFLLVGTADGKLAIFEDKTVKLKGAAPLKILNIGNVS
TPLMCLSESTNSTERNVMWGGCGTKIFSFSNDFTIQKLIETRTSQLFSYA
AFSDSNIITVVVDTALYIAKQNSPVVEVWDKKTEKLCGLIDCVHFLREVS
GRVKTLCLQKNTALWIGTGGGHILLLDLSTRRLIRVIYNFCNSVRVMMTA
QLGSLKNVMLVLGYNRKIQSCLTVWDINLPHEVQNLEKHIEVRKELAEKM
RRTSV
Ligand information
Ligand ID0LI
InChIInChI=1S/C29H27F3N6O/c1-20-5-6-22(16-21(20)8-10-25-18-33-27-4-3-11-34-38(25)27)28(39)35-24-9-7-23(26(17-24)29(30,31)32)19-37-14-12-36(2)13-15-37/h3-7,9,11,16-18H,12-15,19H2,1-2H3,(H,35,39)
InChIKeyPHXJVRSECIGDHY-UHFFFAOYSA-N
SMILES
SoftwareSMILES
CACTVS 3.370CN1CCN(CC1)Cc2ccc(NC(=O)c3ccc(C)c(c3)C#Cc4cnc5cccnn45)cc2C(F)(F)F
ACDLabs 12.01FC(F)(F)c1cc(ccc1CN2CCN(C)CC2)NC(=O)c5cc(C#Cc3cnc4cccnn34)c(cc5)C
OpenEye OEToolkits 1.7.6Cc1ccc(cc1C#Cc2cnc3n2nccc3)C(=O)Nc4ccc(c(c4)C(F)(F)F)CN5CCN(CC5)C
FormulaC29 H27 F3 N6 O
Name3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide;
Ponatinib
ChEMBLCHEMBL1171837
DrugBankDB08901
ZINCZINC000036701290
PDB chain8u8a Chain C Residue 2601 [Download ligand structure] [Download structure with residue number starting from 1] [View ligand structure]
Receptor-Ligand Complex Structure
Global viewLocal viewStructure summary

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PDB8u8a Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM.
Resolution3.4 Å
Binding residue
(original residue number in PDB)		F1890 A1904 K1906 E1920 M1947 L1949 A1950 I1991 Y1992 L2001 A2016 D2017
Binding residue
(residue number reindexed from 1)		F1130 A1144 K1146 E1160 M1187 L1189 A1190 I1231 Y1232 L1241 A1256 D1257
Annotation score1
Enzymatic activity
Enzyme Commision number 2.7.11.1: non-specific serine/threonine protein kinase.
3.6.5.-
Gene Ontology
Molecular Function
GO:0000149 SNARE binding
GO:0000287 magnesium ion binding
GO:0003779 actin binding
GO:0003924 GTPase activity
GO:0004672 protein kinase activity
GO:0004674 protein serine/threonine kinase activity
GO:0004706 JUN kinase kinase kinase activity
GO:0004709 MAP kinase kinase kinase activity
GO:0005096 GTPase activator activity
GO:0005515 protein binding
GO:0005524 ATP binding
GO:0005525 GTP binding
GO:0008017 microtubule binding
GO:0015631 tubulin binding
GO:0016301 kinase activity
GO:0016787 hydrolase activity
GO:0017075 syntaxin-1 binding
GO:0030159 signaling receptor complex adaptor activity
GO:0030276 clathrin binding
GO:0031267 small GTPase binding
GO:0034211 GTP-dependent protein kinase activity
GO:0036479 peroxidase inhibitor activity
GO:0039706 co-receptor binding
GO:0042802 identical protein binding
GO:0042803 protein homodimerization activity
GO:0044024 histone H2AS1 kinase activity
GO:0044325 transmembrane transporter binding
GO:0051018 protein kinase A binding
GO:0106310 protein serine kinase activity
GO:1904713 beta-catenin destruction complex binding
Biological Process
GO:0000165 MAPK cascade
GO:0001934 positive regulation of protein phosphorylation
GO:0006338 chromatin remodeling
GO:0006468 protein phosphorylation
GO:0006606 protein import into nucleus
GO:0006897 endocytosis
GO:0006914 autophagy
GO:0006979 response to oxidative stress
GO:0007005 mitochondrion organization
GO:0007029 endoplasmic reticulum organization
GO:0007030 Golgi organization
GO:0007040 lysosome organization
GO:0007154 cell communication
GO:0007165 signal transduction
GO:0007254 JNK cascade
GO:0007266 Rho protein signal transduction
GO:0007283 spermatogenesis
GO:0007528 neuromuscular junction development
GO:0008104 protein localization
GO:0008340 determination of adult lifespan
GO:0009267 cellular response to starvation
GO:0009966 regulation of signal transduction
GO:0010468 regulation of gene expression
GO:0010506 regulation of autophagy
GO:0010508 positive regulation of autophagy
GO:0010955 negative regulation of protein processing
GO:0010977 negative regulation of neuron projection development
GO:0014041 regulation of neuron maturation
GO:0016242 negative regulation of macroautophagy
GO:0016310 phosphorylation
GO:0018105 peptidyl-serine phosphorylation
GO:0018107 peptidyl-threonine phosphorylation
GO:0019722 calcium-mediated signaling
GO:0021756 striatum development
GO:0021772 olfactory bulb development
GO:0022028 tangential migration from the subventricular zone to the olfactory bulb
GO:0030154 cell differentiation
GO:0030182 neuron differentiation
GO:0031398 positive regulation of protein ubiquitination
GO:0031647 regulation of protein stability
GO:0032091 negative regulation of protein binding
GO:0032092 positive regulation of protein binding
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process
GO:0032760 positive regulation of tumor necrosis factor production
GO:0034260 negative regulation of GTPase activity
GO:0034599 cellular response to oxidative stress
GO:0034614 cellular response to reactive oxygen species
GO:0035556 intracellular signal transduction
GO:0035564 regulation of kidney size
GO:0035640 exploration behavior
GO:0035641 locomotory exploration behavior
GO:0035751 regulation of lysosomal lumen pH
GO:0040012 regulation of locomotion
GO:0042391 regulation of membrane potential
GO:0043068 positive regulation of programmed cell death
GO:0043406 positive regulation of MAP kinase activity
GO:0045746 negative regulation of Notch signaling pathway
GO:0045860 positive regulation of protein kinase activity
GO:0046039 GTP metabolic process
GO:0046777 protein autophosphorylation
GO:0048312 intracellular distribution of mitochondria
GO:0048812 neuron projection morphogenesis
GO:0051646 mitochondrion localization
GO:0051770 positive regulation of nitric-oxide synthase biosynthetic process
GO:0051900 regulation of mitochondrial depolarization
GO:0051966 regulation of synaptic transmission, glutamatergic
GO:0060070 canonical Wnt signaling pathway
GO:0060079 excitatory postsynaptic potential
GO:0060159 regulation of dopamine receptor signaling pathway
GO:0060161 positive regulation of dopamine receptor signaling pathway
GO:0060628 regulation of ER to Golgi vesicle-mediated transport
GO:0060828 regulation of canonical Wnt signaling pathway
GO:0061001 regulation of dendritic spine morphogenesis
GO:0070585 protein localization to mitochondrion
GO:0070973 protein localization to endoplasmic reticulum exit site
GO:0071287 cellular response to manganese ion
GO:0071407 cellular response to organic cyclic compound
GO:0090140 regulation of mitochondrial fission
GO:0090263 positive regulation of canonical Wnt signaling pathway
GO:0090394 negative regulation of excitatory postsynaptic potential
GO:0140058 neuron projection arborization
GO:0141161 regulation of cAMP/PKA signal transduction
GO:1900242 regulation of synaptic vesicle endocytosis
GO:1900244 positive regulation of synaptic vesicle endocytosis
GO:1902236 negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway
GO:1902499 positive regulation of protein autoubiquitination
GO:1902692 regulation of neuroblast proliferation
GO:1902803 regulation of synaptic vesicle transport
GO:1902823 negative regulation of late endosome to lysosome transport
GO:1902902 negative regulation of autophagosome assembly
GO:1903125 negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation
GO:1903215 negative regulation of protein targeting to mitochondrion
GO:1903217 negative regulation of protein processing involved in protein targeting to mitochondrion
GO:1903351 cellular response to dopamine
GO:1903980 positive regulation of microglial cell activation
GO:1904887 Wnt signalosome assembly
GO:1905279 regulation of retrograde transport, endosome to Golgi
GO:1905289 regulation of CAMKK-AMPK signaling cascade
GO:2000172 regulation of branching morphogenesis of a nerve
GO:2000300 regulation of synaptic vesicle exocytosis
GO:2000377 regulation of reactive oxygen species metabolic process
Cellular Component
GO:0000139 Golgi membrane
GO:0005615 extracellular space
GO:0005737 cytoplasm
GO:0005739 mitochondrion
GO:0005741 mitochondrial outer membrane
GO:0005743 mitochondrial inner membrane
GO:0005759 mitochondrial matrix
GO:0005764 lysosome
GO:0005768 endosome
GO:0005783 endoplasmic reticulum
GO:0005789 endoplasmic reticulum membrane
GO:0005794 Golgi apparatus
GO:0005798 Golgi-associated vesicle
GO:0005802 trans-Golgi network
GO:0005829 cytosol
GO:0005856 cytoskeleton
GO:0005886 plasma membrane
GO:0005902 microvillus
GO:0008021 synaptic vesicle
GO:0030424 axon
GO:0030425 dendrite
GO:0030426 growth cone
GO:0030672 synaptic vesicle membrane
GO:0031410 cytoplasmic vesicle
GO:0031966 mitochondrial membrane
GO:0032473 cytoplasmic side of mitochondrial outer membrane
GO:0032839 dendrite cytoplasm
GO:0042995 cell projection
GO:0043005 neuron projection
GO:0043025 neuronal cell body
GO:0043195 terminal bouton
GO:0043204 perikaryon
GO:0043231 intracellular membrane-bounded organelle
GO:0044753 amphisome
GO:0044754 autolysosome
GO:0045121 membrane raft
GO:0045202 synapse
GO:0045335 phagocytic vesicle
GO:0070062 extracellular exosome
GO:0070971 endoplasmic reticulum exit site
GO:0097487 multivesicular body, internal vesicle
GO:0098794 postsynapse
GO:0098978 glutamatergic synapse
GO:0099400 caveola neck
GO:0099523 presynaptic cytosol
GO:1990904 ribonucleoprotein complex
GO:1990909 Wnt signalosome

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Molecular Function
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Biological Process
View graph for
Cellular Component
External links
PDB RCSB:8u8a, PDBe:8u8a, PDBj:8u8a
PDBsum8u8a
PubMed38263358
UniProtQ5S007|LRRK2_HUMAN Leucine-rich repeat serine/threonine-protein kinase 2 (Gene Name=LRRK2)

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