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Lecture

SEGREGATION of KINETIC REACTIVITY & BINDING AFFINITY

In course

CH-412: Frontiers in chemical biology

Chemical biology is a key discipline in biomedical research for drug discovery, synthetic biology and protein functional annotation. We will give a broad perspective of the field ranging from seminal classical experiments to state-of-the-art approaches to ...

Description

The paper focuses on the importance of reversible interactions to potency and mechanisms of drug resistance. It discusses the systematic assessment of non-covalent binding and chemical reactivity components to the ultimate clinical potency of emerging covalent kinase drugs. The authors deconvolute contributions from the 'reversible' component of a covalent drug, and the assay readout is considered. The study evaluates the kinetic analysis of covalent inhibition of EGFR- L858R/T790M, a disease-relevant double mutant. The data shows the kinetic analysis of various inhibitors and their impact on EGFR mutants.

Official source

Ontological neighbourhood

Biology

Cell biology: Cell signaling

Related concepts (32)

Tyrosine kinase

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger class of enzymes known as protein kinases which also attach phosphates to other amino acids such as serine and threonine. Phosphorylation of proteins by kinases is an important mechanism for communicating signals within a cell (signal transduction) and regulating cellular activity, such as cell division.

Kinase

In biochemistry, a kinase (ˈkaɪneɪs,ˈkɪneɪs,-eɪz) is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. This transesterification produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group (producing a dephosphorylated substrate and the high energy molecule of ATP).

Protein kinase

A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase.

Janus kinase

Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2 (since they were just two of many discoveries in a PCR-based screen of kinases), but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of beginnings, endings and duality, Janus, because the JAKs possess two near-identical phosphate-transferring domains.

Receptor tyrosine kinase

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer.

Related lectures (31)

Protein Phosphorylation: Mechanisms & Regulation

Explores protein phosphorylation, detailing common modifications like acetylation and ubiquitination, kinase specificity, and activation mechanisms.

Protein Phosphorylation: Mechanisms and Regulation

Explores protein phosphorylation, its structural effects, kinase activity, and its role in signaling and disease.

Posttranslational Modifications: Phosphorylation and Protein Phosphatases

Covers posttranslational modifications, focusing on phosphorylation and protein phosphatases, and explains kinase specificity assays and the optimal phosphorylation consensus.

Tyrosine Kinases & Ras Signaling

Explores tyrosine kinases, Ras activation, lipid signaling, cancer implications, and signal transduction in cells.

Altered Pathways in Cancer: Signaling Cascades and Mutations