Mutation Structure Flashcards
What is epidermal growth factor receptor?
EGF binds to the extracellular domain of EGFR. Ligand-EGFR complex forms an asymmetric dimer. Intracellular kinase domain autophosphorylares. SH2 domain Domains of signaling proteins bind to phospoTyr and trigger signaling cascades trigger proliferation, migration and adhesion.
EGFR is upregulated in colon, head and neck tumours.
EGFR responds to the binding of the ligand, this leads to phoosphorylation.
Phorsphorylation enables other signalling proteins to recognise the phosphoserine on the receptor and bind to it leading to a downstram signalling response.
How is EGFR implicated in the development and progression of cancer?
Overexpression of EGFR and activating mutation in extracellular or intracellular domains.
Mutations in the extracellular domain lead to an constitively active.
Mutations in the kinase domain are found in subset of NSCLC.
These mutations are driver mutations - they confer with the growth advantage so drive cancer.
what are the two conformations of EGFR kinase domain?
Active and inactive.
Inactive confirmation has two hallmarks found in many inactive kinase structures. Asymmetric dimerisation creates physical pressure on the kinase to push it from the active to inactive confirmation.
How is the inactive confirmation stabilised?
It is stabilised by hydrophobic cluster. In the active conformation the sidechain of Leu858 is solvent exposed. Two of the hydrophobic residues form active hydrophobic spine with conserved Phe and His. Mutating Leu858 to Arg destabilises and promotes active confirmation.
There is increased stability in the active form compared to the inactive.
What are gatekeeper mutations in EGFR?
Thr790 and the T790M mutation. Once this mutation occurs patients must move from gefitinib to a second line therapy. It is a mutation where patients develop resistance to gefitinib, through structurally converse residue called a gatekeeper to a bulkier residue.
