Proto-oncogene tyrosine-protein kinase

Non-receptor proto-oncogene tyrosine-protein kinase (NTPK) are enzymes which transfer a phosphate group from ATP to proteins. Protein tyrosine kinases are critical cell signaling enzymes. These enzymes have a highly conserved Arg residue in their catalytic loop which is present two residues or four residues downstream from an absolutely conserved Asp catalytic base. Prior studies on protein tyrosine kinases Csk and Src revealed the potential for chemical rescue of catalytically deficient mutant kinases (Arg to Ala mutations) by small diamino compounds, particularly imidazole; however, the potency and efficiency of rescue was greater for Src. This current study further examines the structural and kinetic basis of rescue for mutant Src as compared to mutant Abl tyrosine kinase. An X-ray crystal structure of R388A Src revealed the surprising finding that a histidine residue of the N-terminus of a symmetry-related kinase inserts into the active site of the adjacent Src and mimics the hydrogen-bonding pattern seen in wild-type protein tyrosine kinases. Abl R367A shows potent and efficient rescue more comparable to Src, even though its catalytic loop is more like that of Csk. Various enzyme redesigns of the active sites indicate that the degree and specificity of rescue are somewhat flexible, but the overall properties of the enzymes and rescue agents play an overarching role. The newly discovered rescue agent 2-aminoimidazole is about as efficient as imidazole in rescuing R/A Src and Abl. Rate vs pH studies with these imidazole analogues suggest that the protonated imidazolium is the preferred form for chemical rescue, consistent with structural models. The efficient rescue seen with mutant Abl points to the potential of this approach to be used effectively to analyze Abl phosphorylation pathways in cells. Ref. 1

Src from Gallus gallus contains 1 protein kinase domain, 1 SH2 domain, and 1 SH3 domain. 3GEQ becomes activated when its major tyrosine phosphorylation site is not phosphorylated. Phosphorylation occurs on Tyr-527 by c-Src kinase (CSK); the phosphorylated form is termed pp60c-src. The phosphorylated tail interacts with the SH2 domain thereby repressing kinase activity. It can also be activated by point mutations as well as by truncations at the C-terminal end or by other mutations.

Its subunit structure forms a complex with polyoma virus middle T antigen and interacts with AFAP-110. Interacts with IGF2BP1 Ref. 3. Additionally, it is widely expressed to high levels, and with a high degree of kinase activity in certain fully differentiated cells such as neurons, platelets and macrophages. Isoform 1 is widely expressed. Isoform 2 is expressed only in the muscle.

For details of Proto-oncogene tyrosine-protein kinase SRC see SRC.

3D structures of proto-oncogene tyrosine-protein kinase

Updated on 02-July-2013

Proto-oncogene tyrosine-protein kinase Src

3lok, 3geq, 2qi8, 3of0 – cNTPK SRC kinase domain (mutant) – chicken

3fj5 - cNTPK SRC SH3 domain
1f2f - cNTPK SRC SH2 domain (mutant)
1yi6 – hNTPK SRC C terminal - human
1yoj - hNTPK SRC kinase domain (mutant)
1fmk - hNTPK SRC kinase, SH2, SH3, C terminal domains
1k9a – CSK – rat
3eac – hCSK SH2 domain
3eaz – hCSK SH2 domain (mutant)

Binary complex

1p13 - cNTPK SRC SH2 domain + peptide

1f1w - cNTPK SRC SH2 domain (mutant) + phosphopeptide
3g6g, 3f6x, 3el7, 3el8, 3en4, 3en5, 3en6, 3en7, 2hwo, 2hwp - cNTPK SRC kinase domain + inhibitor
3f3v, 3f3w, 3g6h, 3f3t, 3f3u, 2qlq, 2qq7, 3oez, 3svv - cNTPK SRC kinase domain (mutant) + inhibitor
3g5d - cNTPK SRC kinase domain (mutant) + cancer drug
2oiq - cNTPK SRC kinase domain + cancer drug
3dqw - cNTPK SRC kinase domain (mutant) + ATPγS
3dqx - cNTPK SRC kinase domain + ATPγS
3d7t - cNTPK SRC kinase domain + inactivator CSK (mutant)
3d7u - cNTPK SRC kinase domain + inactivator CSK
2h8h, 2bdf, 2bdj – hNTPK SRC + inhibitor – human
1yol, 1yom - hNTPK SRC kinase domain (mutant) + inhibitor
1y57 - hNTPK SRC kinase, SH2, SH3 domains + inhibitor
1ksw - hNTPK SRC kinase, SH2, SH3 domains (mutant) + benzyl ADP
1o41, 1o42, 1o43, 1o44, 1o45, 1o46, 1o47, 1o48, 1o49, 1o4a, 1o4b, 1o4c, 1o4d, 1o4e, 1o4f, 1o4g, 1o4h, 1o4j, 1o4i, 1o4k, 1o4l, 1o4m, 1o4n, 1o4o, 1o4p, 1o4q, 1o4r - hNTPK SRC SH2 domain + inhibitor
2src - hNTPK SRC kinase, SH2, SH3, C terminal domains + AMP-PNP
1byg - hCSK kinase domain + staurosporine
1a07, 1a08, 1a09, 1a1a, 1a1b, 1a1c, 1a1e - hCSK SH2 domain + peptide ligand
1shd - hCSK SH2 domain + peptide inhibitor
1prl, 1prm, 1rlp, 1rlq - hCSK SH3 domain + peptide ligand
1jeg – CSK SH3 domain + protein-tyrosine phosphatase peptide – mouse

Proto-oncogene tyrosine-protein kinase Lck

See Lymphocyte-specific tyrosine kinase in Tyrosine kinase

Proto-oncogene tyrosine-protein kinase FYN

3h0f, 3h0h, 3h0i, 3cqt - hNTPK FYN SH3 domain (mutant)

1zbj - hNTPK FYN SH3 domain – NMR
1g83 - hNTPK FYN SH2, SH3 domains (mutant)

Binary complex

2dq7 - hNTPK FYN kinase domain + antibiotic

1m27 - hNTPK FYN SH3 domain + SH2 domain protein 1A + SLAM

Proto-oncogene tyrosine-protein kinase ABL1

3eg0, 3eg2, 3eg3, 3egu - hNTPK ABL1 SH3 domain (mutant)

2fo0 - hNTPK ABL1 SH2]], SH3 domains (mutant)
1zzp - hNTPK ABL1 F-actin binding domain – NMR
1opj, 1opk, 1opl - mNTPK ABL1 kinase domain – mouse

Binary complex

3eg1, 2o88 - hNTPK ABL1 SH3 domain (mutant) + peptide

1ju5 - hNTPK ABL1 SH3 domain + CRK SH2 domain + CRK phosphopeptide - NMR
3k2m - hNTPK ABL1 SH2 domain + monobody A4
2e2b, 2hiw - hNTPK ABL1 kinase domain + inhibitor
2f4j - hNTPK ABL1 kinase domain (mutant) + inhibitor
3cs9, 2hyy, 2hz0, 2hz4, 2hzi, 2hzn, 2gqg - hNTPK ABL1 kinase domain + cancer drug
2g1t - hNTPK ABL1 kinase domain + peptide
3ik3, 1m52, 1fpu - mNTPK ABL1 kinase domain + inhibitor
1iep - mNTPK ABL1 kinase domain + cancer drug
3dk3, 3dk6, 3dk7, 2qoh, 2v7a, 2z60 - mNTPK ABL1 kinase domain (mutant) + inhibitor

Proto-oncogene tyrosine-protein kinase FER

2kk6 - hNTPK FER SH2 domain

Proto-oncogene tyrosine-protein kinase KIT

2ec8 - hNTPK KIT extracellular domain

Binary complex

3g0e, 3g0f - hNTPK KIT kinase domain (mutant) + cancer drug

2e9w, 2o26 - hNTPK KIT extracellular domain + stem cell factor

Proto-oncogene tyrosine-protein kinase FES

3bkb - hNTPK FES kinase, SH2 domains

2dcr, 1wqu - hNTPK FES SH2 domain – NMR

Binary complex

3cd3, 3cbl - hNTPK FES kinase, SH2 domains + peptide

Proto-oncogene tyrosine-protein kinase MER

2p0c - hNTPK MER kinase domain

2dbj - hNTPK MER precursor fibronectin domain – NMR

Binary complex

3bpr - hNTPK MER kinase domain + inhibitor

3brb - hNTPK MER kinase domain + ADP

Proto-oncogene tyrosine-protein kinase YES

2hda - hNTPK YES SH3 domain