Structural studies on cell surface receptors and lipopeptide antibiotics: On Notch1, epidermal growth factor receptor, and laspartomycin C analogues

Abstract

Proteins are universal molecular machines that are involved in the biological processes of all living organisms, from animals to bacteria. Proteins are constituted of building blocks, called amino acids, that are linearly attached to each other. Despite this apparent simplicity, proteins achieve an extraordinary diversity of functions such as cell differentiation and immune response. To do so, proteins adopt a unique three-dimensional shape that allows them to perform a specific task defining their function. A certain type of proteins, called cell surface receptors, play an important role by mediating communication to and from the cell. They sense the cell environment and transmit the received messages into the cell, but can also send messages to other cells. These messages can be exchanged between neighbor cells by direct protein contacts, or between distant cells by secretion of molecules that can travel from one cell to another. These processes are tightly regulated throughout the body, and if messages are incorrectly received or sent, diseases may develop. Proteins can also be used to treat pathologies arising from such dysfunction, or from infection by a pathogen. This is the case of the lipopeptide calcium-dependent antibiotics, which help fight bacterial infections. These compounds target specific molecules on the bacterial membrane and operate by destabilizing the membrane or by preventing the cell wall synthesis. In this thesis, we combine diverse structural biology approaches and use tools with clinical potential to gain insight into the structure and function of cell surface receptors and lipopeptide calcium-dependent antibiotics, to ultimately help develop therapeutic molecules to treat the associated diseases.