IISER Pune
INDIAN INSTITUTE OF SCIENCE EDUCATION AND RESEARCH (IISER) PUNE
where tomorrow’s science begins today
An Autonomous Institution, Ministry of Human Resource Development, Govt. of India
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Seminars and Colloquia

Biology

Acetylcholine receptor in action: sniff, bind, gate and open 
 
Tue, Feb 27, 2018,   12:00 PM to 01:00 PM at Seminar Room 34, 2nd Floor, Main Building

Dr. Tapan Kumar Nayak
SUNY at Buffalo, New York, USA

How does ligand binding activate an ‘allosteric’ receptor and what structural elements recognize a ligand? Protein-ligand interaction studies are essential for understanding protein function and for potential therapeutic development. I use patch-clamp, protein engineering, thermodynamics and molecular simulations to understand agonist binding and ‘gating’ (global conformational change that leads to channel opening) in neuromuscular acetylcholine receptors (AChRs). My work suggests that in AChRs, agonist ‘affinity’ is determined by a conserved core of five aromatic residues. However, affinity can be engineered by modulating the outer-zone residues at the binding site. Ligand binding either precedes (conformational selection) or follows (induced-fit) a local conformational change depending on the state of the binding site (closed vs open). ‘Efficacy’ of the receptor is a function of the agonist energy (owing to affinity) and the intrinsic gating energy. Constitutive channel activity is a manifestation of the intrinsic gating energy. Mutations, including those that cause diseases, and the allosteric modulators only resettle the intrinsic gating of the receptor locally. Allosteric communication from the orthosteric agonist site (50 Å away) is transmitted as a ‘conformational wave’ to the ion channel pore. The mechanism of allosteric communication will be discussed in the light of intermediates in the transition state ensemble.

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