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DrugBank target: P00519

DrugBank target: P00519 (ABL1_HUMAN)     

Example drug-target structure: 2gqg

( There are 55 structures corresponding to this UniProt sequence in the PDB. Click the orange, plus icon above for a list. )

Tyrosine-protein kinase ABL1

Abelson murine leukemia viral oncogene homolog 1, Abelson tyrosine-protein kinase 1, Proto-oncogene c-Abl, p150.

Function

Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage- induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin- associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1..

Enzyme

2.7.10.2   [EC->PDB]   [IntEnz]   [ExPASy]   [KEGG]  

Catalytic activity

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

Disease(s)

Leukemia, chronic myeloid (CML) [MIM:608232]: A clonal myeloproliferative disorder of a pluripotent stem cell with a specific cytogenetic abnormality, the Philadelphia chromosome (Ph), involving myeloid, erythroid, megakaryocytic, B-lymphoid, and sometimes T-lymphoid cells, but not marrow fibroblasts. Note=The gene represented in this entry is involved in disease pathogenesis.
Note=A chromosomal aberration involving ABL1 has been found in patients with chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

Schematic diagram of Pfam domains in target sequence plus wiring diagrams of PDB structures containing drug molecules

2gqg
3ue4
2hyy
3cs9

Key:    PfamA domain  PfamB domain  Secondary structure  Bound drug molecule

Sequence length: 1129 a.a.

Approved drugs / nutraceuticals targeting this protein

The DrugBank database identifies 6 drugs and and 1 nutraceutical for this target protein:

 

Generic name: DB01254 dasatinib
1N1
Formula: C22H26Cln7O2S
Structure: There are 10 PDB structures containing this molecule of which 1 is bound to the above target protein.
Generic name: DB06616 bosutinib
DB8
Formula: C26H29Cl2N5O3
Structure: There are 7 PDB structures containing this molecule of which 1 is bound to the above target protein.
Generic name: DB08901 ponatinib
0LI
Formula: C29H27F3N6O
Structure: There are 4 PDB structures containing this molecule although none are bound to the above target protein.
 
Generic name: DB08896 regorafenib
Formula: C21H15Clf4N4O3
Structure: There are no structures of this molecule in the PDB.
Generic name: DB00619 imatinib
STI
Formula: C29H31N7O
Structure: There are 16 PDB structures containing this molecule of which 2 are bound to the above target protein.
Generic name: DB04868 nilotinib
NIL
Formula: C28H22F3N7O
Structure: There are 2 PDB structures containing this molecule of which 1 is bound to the above target protein.
Generic name: DB00171 adenosine triphosphate
ATP
Formula: C10H16N5O13P3
Structure: There are 844 PDB structures containing this molecule although none are bound to the above target protein.

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