Target Information
| Target General Information | Top | |||||
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| Target ID |
T32764
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| Target Name |
Adaptor-associated kinase 1 (AAK1)
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| Synonyms |
Adaptor-associated kinase 1
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| Gene Name |
AAK1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | General pain disorder [ICD-11: 8E43] | |||||
| Function |
Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis. Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1. Regulates phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes. Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes. Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.1
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| Sequence |
MKKFFDSRREQGGSGLGSGSSGGGGSTSGLGSGYIGRVFGIGRQQVTVDEVLAEGGFAIV
FLVRTSNGMKCALKRMFVNNEHDLQVCKREIQIMRDLSGHKNIVGYIDSSINNVSSGDVW EVLILMDFCRGGQVVNLMNQRLQTGFTENEVLQIFCDTCEAVARLHQCKTPIIHRDLKVE NILLHDRGHYVLCDFGSATNKFQNPQTEGVNAVEDEIKKYTTLSYRAPEMVNLYSGKIIT TKADIWALGCLLYKLCYFTLPFGESQVAICDGNFTIPDNSRYSQDMHCLIRYMLEPDPDK RPDIYQVSYFSFKLLKKECPIPNVQNSPIPAKLPEPVKASEAAAKKTQPKARLTDPIPTT ETSIAPRQRPKAGQTQPNPGILPIQPALTPRKRATVQPPPQAAGSSNQPGLLASVPQPKP QAPPSQPLPQTQAKQPQAPPTPQQTPSTQAQGLPAQAQATPQHQQQLFLKQQQQQQQPPP AQQQPAGTFYQQQQAQTQQFQAVHPATQKPAIAQFPVVSQGGSQQQLMQNFYQQQQQQQQ QQQQQQLATALHQQQLMTQQAALQQKPTMAAGQQPQPQPAAAPQPAPAQEPAIQAPVRQQ PKVQTTPPPAVQGQKVGSLTPPSSPKTQRAGHRRILSDVTHSAVFGVPASKSTQLLQAAA AEASLNKSKSATTTPSGSPRTSQQNVYNPSEGSTWNPFDDDNFSKLTAEELLNKDFAKLG EGKHPEKLGGSAESLIPGFQSTQGDAFATTSFSAGTAEKRKGGQTVDSGLPLLSVSDPFI PLQVPDAPEKLIEGLKSPDTSLLLPDLLPMTDPFGSTSDAVIEKADVAVESLIPGLEPPV PQRLPSQTESVTSNRTDSLTGEDSLLDCSLLSNPTTDLLEEFAPTAISAPVHKAAEDSNL ISGFDVPEGSDKVAEDEFDPIPVLITKNPQGGHSRNSSGSSESSLPNLARSLLLVDQLID L Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | LX9211 | Drug Info | Phase 1 | Neuropathic pain | [1] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | LX9211 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Intedanib | Ligand Info | |||||
| Structure Description | Crystal Structure of Adaptor Protein 2 Associated Kinase (AAK1) in complex with BIBF 1120 | PDB:5TE0 | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [2] |
| PDB Sequence |
MTSGLGSGYI
35 GRVFGIGRQQ45 VTVDEVLAEG55 GFAIVFLVRT65 SNGMKCALKR75 MFVNNEHDLQ 85 VCKREIQIMR95 DLSGHKNIVG105 YIDSSINNVV119 WEVLILMDFC129 RGGQVVNLMN 139 QRLQTGFTEN149 EVLQIFCDTC159 EAVARLHQCK169 TPIIHRDLKV179 ENILLHDRGH 189 YVLCDFGSAT199 NKFQNPQTEG209 VNAVEDEIKK219 YTTLSYRAPE229 MVNLYSGKII 239 TTKADIWALG249 CLLYKLCYFT259 LPFGESQVAI269 CDGNFTIPDN279 SRYSQDMHCL 289 IRYMLEPDPD299 KRPDIYQVSY309 FSFKLLKKEC319 PIPNVQNSPI329 PAKLPEPVKA 339 SEAAAK
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GLU50
2.391
LEU52
2.557
ALA53
2.176
VAL60
2.468
LEU62
2.585
LYS70
4.857
ALA72
2.997
LYS74
3.485
GLU90
3.266
MET94
2.330
SER98
4.491
VAL104
2.408
ILE124
3.798
MET126
2.801
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| Ligand Name: K252a | Ligand Info | |||||
| Structure Description | Crystal Structure of Adaptor Protein 2 Associated Kinase (AAK1) in complex with small molecule inhibitor | PDB:4WSQ | ||||
| Method | X-ray diffraction | Resolution | 1.95 Å | Mutation | No | [3] |
| PDB Sequence |
GLGSGYIGRV
38 FGIGRQQVTV48 DEVLAEGGFA58 IVFLVRTSNG68 MKCALKRMFV78 NNEHDLQVCK 88 REIQIMRDLS98 GHKNIVGYID108 SSINNVSSGD118 VWEVLILMDF128 CRGGQVVNLM 138 NQRLQTGFTE148 NEVLQIFCDT158 CEAVARLHQC168 KTPIIHRDLK178 VENILLHDRG 188 HYVLCDFGSA198 TNKFQNPQTE208 GVNAVEDEIK218 KYTTLSYRAP228 EMVNLYSGKI 238 ITTKADIWAL248 GCLLYKLCYF258 TLPFGESQVA268 ICDGNFTIPD278 NSRYSQDMHC 288 LIRYMLEPDP298 DKRPDIYQVS308 YFSFKLLKKE318 CPIPNVQNSP328 IPAKLPEPVK 338 ASEAAAK
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Biological Network Descriptors
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Degree | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 2.84E-05 |
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| Closeness centrality | 1.93E-01 | Radiality | 1.33E+01 | Clustering coefficient | 3.33E-01 |
| Neighborhood connectivity | 1.90E+01 | Topological coefficient | 4.06E-01 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 2 | Crystal Structure of Adaptor Protein 2 Associated Kinase (AAK1) in complex with BIBF 1120 | |||||
| REF 3 | Family-wide Structural Analysis of Human Numb-Associated Protein Kinases. Structure. 2016 Mar 1;24(3):401-11. | |||||
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