Imagine an inhibitor of a receptor tyrosine kinase that acts on the kinase domai
ID: 167731 • Letter: I
Question
Imagine an inhibitor of a receptor tyrosine kinase that acts on the kinase domain to competitively inhibit its activity. This inhibitor is an analog of the substrate peptide that normally gets phosphorylated on the serine residue in the middle of the following sequence:
...-Ala-Asp-Ser-Gly-His-...
The inhibitor looks just like the sequence above, but It has a non-hydrolyzable analog of ATP (AMP-PNP: http://www.sigmaaldrich.com/catalog/product/roche/10102547001?lang=en®ion=US ) fused to the serine side-chain.
a. What would be the molecular weight of this inhibitor? (400-500, 500- 600, 700, 800, 900, 1000)
b. This inhibitor have more than 10 H-bond acceptors? (T/F)c.
c. This inhibitor would have at least five H-bond donors on the peptide portion of the molecule? (T/F)
d. Since it contains a non-hyrolyzable ATP analog, this inhibitor would likely be very poisonous, because it would bind many ATP-utilizing enzymes, such as the RNA polymerase II. (T/F)
e. Without any modifications, this inhibitor would have a positive charge on the N-terminal side of the paptide portion, a negative charge on the C-terminus of the peptide portion, and three negative charges on the ATP analog. (T/F)
f. This inhibitor is likely to be very rigid and bind its target kinase enzyme in a preorganized conformation (T/F)
g. To make the inhibitor more membrane-permeable, you could change the two carboxylates into methyl esters to mask their charge. The esters would not bind the target, but may be hydrolyzed by a cellular esterase to reveal the active inhibitor. This strategy would improve the permeability of the precursor of the inhibitor and is a viable general strategy for improving the pharmacokinetics of drug candidates.(T/F)
Explanation / Answer
a) The molecular weight will be around 1000. The analogue is having the mol. wt. of 506, ala=85, asp=133, ser=105, gly=75, his=155. The total comes 1059, but during born formation dehydration has occured, a total of 5 water molecules were removed. (molecular weight of water is 18, so 18x5=90), So 1059-90= 969.
b) False. The number would be lesser.
c) True. The -NH group of amino acids will act as H-bond donors.
d) True. The ATP analogue can also interfere with DNA synthesis.