The Resistance Tetrad

Bailey, Fiona P.; Andreev, Veselin I.; Eyers, Patrick A.

doi:10.1016/b978-0-12-397918-6.00005-7

Cited by 17 publications

(10 citation statements)

References 111 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, it has recently been appreciated that amino acids adjacent to the DFG motif, including the DFG −1 residue (conserved as glutamic acid in TRB pseudokinases; Figure 5C) or the DFG +1 residue (conserved as aspartic acid in TRB pseudokinases; Figure 5C) are also critical for several features of active kinase conformations, catalysis or sensitivity to clinical kinase inhibitors [93]. For example, in both size and chemical nature, the DFG −1 residue and the gatekeeper residue impart structural restrictions on how small molecules drive the active and inactive conformation of several model kinases [84].…”

Section: Discussionmentioning

confidence: 99%

“…PP1 analogues), since they cannot access a hydrophobic cavity located within the ATP-binding pocket. Most clinically approved kinase inhibitors target kinases with a small (threonine) gatekeeper residue, although only ∼20% of the human kinome have evolved a serine/threonine amino acid in this position [93]. No human kinase possesses the smallest amino acid side-chains (glycine or alanine) and following mutation to either of these residues, the enlarged ATP-binding pockets of such AS gatekeeper kinases now possess the ability to specifically interact with bulky kinase inhibitor analogues, which have the enormous advantage of being unable to target the vast majority of kinase ATP-binding sites in endogenous protein kinases [94].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner

Bailey

Byrne

Oruganty

et al. 2015

Biochemical Journal

View full text Add to dashboard Cite

The human Tribbles (TRB)-related pseudokinases are CAMK (calcium/calmodulin-dependent protein kinase)-related family members that have evolved a series of highly unusual motifs in the ‘pseudocatalytic’ domain. In canonical kinases, conserved amino acids bind to divalent metal ions and align ATP prior to efficient phosphoryl-transfer to substrates. However, in pseudokinases, atypical residues give rise to diverse and often unstudied biochemical and structural features that are thought to be central to cellular functions. TRB proteins play a crucial role in multiple signalling networks and overexpression confers cancer phenotypes on human cells, marking TRB pseudokinases out as a novel class of drug target. In the present paper, we report that the human pseudokinase TRB2 retains the ability to both bind and hydrolyse ATP weakly in vitro. Kinase activity is metal-independent and involves a catalytic lysine residue, which is conserved in TRB proteins throughout evolution alongside several unique amino acids in the active site. A similar low level of autophosphorylation is also preserved in the closely related human TRB3. By employing chemical genetics, we establish that the nucleotide-binding site of an ‘analogue-sensitive’ (AS) TRB2 mutant can be targeted with specific bulky ligands of the pyrazolo-pyrimidine (PP) chemotype. Our analysis confirms that TRB2 retains low levels of ATP binding and/or catalysis that is targetable with small molecules. Given the significant clinical successes associated with targeting of cancer-associated kinases with small molecule inhibitors, it is likely that similar approaches will be useful for further evaluating the TRB pseudokinases, with the translation of this information likely to furnish new leads for drug discovery.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner

Bailey

Byrne

Oruganty

et al. 2015

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…MbAbl2 has a Gln residue at this position, rather than the Thr that is present in Abl and most tyrosine kinases. The Gln residue at this position of MbAbl2 may also contribute to the high specific activity of this enzyme [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Constitutive Activity in an Ancestral Form of Abl Tyrosine Kinase

2015

View full text Add to dashboard Cite

The c-abl proto-oncogene encodes a nonreceptor tyrosine kinase that is found in all metazoans, and is ubiquitously expressed in mammalian tissues. The Abl tyrosine kinase plays important roles in the regulation of mammalian cell physiology. Abl-like kinases have been identified in the genomes of unicellular choanoflagellates, the closest relatives to the Metazoa, and in related unicellular organisms. Here, we have carried out the first characterization of a premetazoan Abl kinase, MbAbl2, from the choanoflagellate Monosiga brevicollis. The enzyme possesses SH3, SH2, and kinase domains in a similar arrangement to its mammalian counterparts, and is an active tyrosine kinase. MbAbl2 lacks the N-terminal myristoylation and cap sequences that are critical regulators of mammalian Abl kinase activity, and we show that MbAbl2 is constitutively active. When expressed in mammalian cells, MbAbl2 strongly phosphorylates cellular proteins on tyrosine, and transforms cells much more potently than mammalian Abl kinase. Thus, MbAbl2 appears to lack the autoinhibitory mechanism that tightly constrains the activity of mammalian Abl kinases, suggesting that this regulatory apparatus arose more recently in metazoan evolution.

show abstract

“…Since this is the most frequent region of mutations, it is commonly referred to as the "resistance tetrad". Outside of the hinge region, mutations that confer resistance to small molecule inhibitors can occur in the +5 position of the G-loop, or the −/+1 positions of the DFG motif [65].…”

Section: Challenges For Targeting Kinases: Overcoming Resistancementioning

confidence: 99%

Combing the Cancer Genome for Novel Kinase Drivers and New Therapeutic Targets

Torres‐Ayuso

Brognard

2019

Cancers

View full text Add to dashboard Cite

Protein kinases are critical regulators of signaling cascades that control cellular proliferation, growth, survival, metabolism, migration, and invasion. Deregulation of kinase activity can lead to aberrant regulation of biological processes and to the onset of diseases, including cancer. In this review, we focus on oncogenic kinases and the signaling pathways they regulate that underpin tumor development. We highlight genomic biomarker-based precision medicine intervention strategies that match kinase inhibitors alone or in combination to mutationally activated kinase drivers, as well as progress towards implementation of these treatment strategies in the clinic. We also discuss the challenges for identification of novel protein kinase cancer drivers in the genomic era.

show abstract

The Resistance Tetrad

Cited by 17 publications

References 111 publications

The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner

The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner

Constitutive Activity in an Ancestral Form of Abl Tyrosine Kinase

Combing the Cancer Genome for Novel Kinase Drivers and New Therapeutic Targets

Contact Info

Product

Resources

About