HeartAtaK · Targeting the Anti-Target: From Structure to Drug in the heart Kv11.1 channel

Targeting the Anti-Target: From Structure to Drug in the heart Kv11.1 channel

One of the world’s biggest secrets is still the functioning of the human brain. In particular, the development of synapses and neuronal activity is a fundamental process about which we still know very little. In terms of their malfunctioning in neurological disorders, our knowledge is even more scarce as the clinical presentation can be very diverse and patients can display very different symptoms even though they have the same diagnosis as for example very often seen for autism spectrum disorder (ASD). Symptoms of ASD can include, in different levels of severity, deficits in verbal and non-verbal communication, mental retardation, lack of social interaction and patterns of stereotypical behaviour. Whole genome sequencing of patients having ASD revealed that 1% of the patients have a mutation in a gene called patched domain-containing protein 1 (ptchd1). Vice versa, 40% of people having a mutation in ptchd1 develop ASD. Thus, ptchd1 is the important marker gene for mental retardation. However, so far very little is known about the function of ptchd1. The protein is supposed to be a receptor in the hedgehog signalling pathway, a pathway best known for its involvement in the prenatal development and the distinction of body patterns. Thus, a defect gene in this signalling pathway has severe consequences for the individual. During this fellowship, I want to investigate how the signal is received by the receptor and how it is transferred to downstream effectors. To achieve this, one aim of this project is to solve the structure of ptchd1 by cryo-EM. The three-dimensional structure of a protein provides the basis for its function. Understanding the protein’s structure allows us to deduce where the incoming signal will bind and how its three-dimensional structure changes upon signalling. However, the signal seems not to be transferred directly from protein to protein but via a small molecule of still unknown identity. As structures provide only static information, I also want to investigate ptchd1’s biophysical behaviour and its interaction with other proteins in order to understand the whole process of signal transduction. This project will provide the first structural information about an important signalling pathway involved in human prenatal development. The information obtained will further shed light a unique signal transfer mechanism.

Data: CORDIS, © European Union