The human genome encodes 518 different protein kinases, many of which play impor

Question

The human genome encodes 518 different protein kinases, many of which play important roles in disease. For example, protein kinase B (PKB) has been identified as an important anti-cancer target. However, inhibition of structurally similar protein kinases, like protein kinase A (PKA), can lead to toxic side-effects. Structure-based drug design led to the design of a compound (depicted below) that had selectivity for PKB (IC50= 6 nM) over PKA (IC50= 168 nM). Schematics of the important noncovalent interactions between the compound and PKA (left) and PKB (right) are depicted below

The human genome encodes 518 different protein kinases, many of which play important roles in disease. For example, protein kinase B (PKB) has been identified as an important anti-cancer target. However, inhibition of structurally similar protein kinases, like protein kinase A (PKA), can lead to toxic side-effects. Structure-based drug design led to the design of a compound (depicted below) that had selectivity for PKB (IC50= 6 nM) over PKA (IC50= 168 nM). Schematics of the important noncovalent interactions between the compound and PKA (left) and PKB (right) are depicted below Explain what is meant by a "protein kinase cascade." (3) Give two reasons why the development of drugs targeting the ATP-binding pocket of PKB might be challenging. (4) Give a structural rationale for the difference in the compound's IC50 for PKB versus PKA. Refer to specific noncovalent interactions formed between the small molecule and the proteins.

Explanation / Answer

A kinase is a type of intracellular protein, en enzyme that 'activates' other proteins by giving them a high energy phosphate group.
In a kinase cascade, one kinase can phosphorylate multiple kinases in the next step of the signaling pathway, and each of them can phosphorylate many more kinases leading to the original signal of maybe one activated protein being turned into a huge, non-reversible chain reaction.
Kinase cascades are used to amplify intracellular signals in many pathways, normally from a cell membrane receptor to the nucleus so a cell detects an external change and changes its gene expression in response.

Much of the original therapeutic efforts was directed to block receptor tyrosine kinases (RTKs), which are upstream activators of these pathways. The clinical efficacy of antibodies that inhibit ligand-mediated activation of RTKs

Related Questions

Navigate

• Browse (All)
• Browse T
• Subjects

---

---

Integrity-first tutoring: explanations and feedback only — we do not complete graded work. Learn more.