Chapter 3-Proteins

Question 1

Is the a-helix right handed or left handed?

Answer 1

Right-handed (clockwise coiling)

Question 2

Benefits of studying proteins

Answer 2

1. Better understanding of biology at the molecular level e.g. cancer
2. Develop drugs that target proteins & recombinant protein therapies

Question 3

Difficulties of studying proteins

Answer 3

1. Number of proteins that can be used a drugs is limited

2. Folding and obtaining optimal gene expression in yeast, bacterial systems is challenging

Question 4

4 stages of drug development

Answer 4

1. Target identification (identify and understand weakness of disease)
2. Lead identification (identify possible chemicals that bind to the target. Prove therapeutic concept in lab and in animals)
3. Lead optimisation (identify possible chemicals that bind to target better and understand properties of chemicals used)
4. Candidate drug nominations (clinical trials, process optimisation, formulation optimisation)

Question 5

Describe the BCR-ABL translocation and its implications

Answer 5

• found in chronic myelogenous leukaemia
• N-terminal coding region of ABL and fuses remainder to BCR—> formation of an oncogene
• resultant fusion protein lacks normal negative control of ABL activity, kinase is constitutively active—> cancer
• bcr-abl can be inhibited by gleevec (original name imatinib)

Question 6

Describe the negative feedback regulation of p53 and mdm2

Answer 6

1. Under normal cell conditions, p53 binds to the promoter of mdm2 gene and promotes its transcription and hence expression of mdm2 protein
2. Mdm2 protein binds to p53 and targets it for ubiquitinylation
3. When DNA damage occurs, p53 is phosphorylated and mdm2 is no longer able to bind to it
4. Once DNA repair is complete, p53 is dephosphorylated and mdm2 is once again able to bind to it

Question 7

What is a proteasome

Answer 7

Protein complexes that degrade proteins by proteolysis

Question 8

Describe the proteasome pathway

Answer 8

1. Proteins marked for destruction are tagged by ubiquitin via ubiquitiylation (carried out by ubiquitin ligases e.g. mdm2)
2. Once a protein is tagged with 1 ubiquitin, this signals the ubiquitin ligases to keep tagging on ubiquitin to form a polyubiquitinylation chain
3. Polyubiquitinylated proteins are degraded in proteasomes to form short peptides

Question 9

Describe a-helices

Answer 9

-formed when the CO group of 1 aa residue and the NH group of residue 4 residues away on the same chain are brought into line with each other as the chain coils, encouraging H bonding

Question 10

Describe B-sheets

Answer 10

• consists of 2 or more aa sequences that are arranged adjacently in parallel or antiparallel orientations
• H bonding occurs between the NH and CO groups between the two strands