The brain has Gephyrin, a central scaffolding protein for inhibitory neurotransmitter receptors.
A neurotransmitter receptor is a membrane receptor protein, activated by a neurotransmitter.
A membrane protein interacts with the phospholipid bilayer that encloses the cell and a membrane receptor protein interacts with a chemical in the cells external environment, which binds to the cell.
The development of dimeric peptides inhibits the interaction between gephyrin and these receptors.
It is a process, which is fundamental to numerous synaptic functions and diseases of the brain.
Receptor-derived minimal gephyrin-binding peptides were identified. It displayed exclusive binding towards native gephyrin from brain lysates.
A series of dimeric ligands were designed and synthesized, which led to a remarkable 1220-fold enhancement of the gephyrin affinity.
The crystal structures were visualized in X-ray and the simultaneous dimer-to-dimer binding in atomic detail, revealing compound-specific binding modes.
The molecular basis of the affinity-enhancing effect of multivalent gephyrin inhibitors and novel compounds with therapeutic potential, which will allow further elucidation of the gephyrin-receptor interplay was also defined.