Enzyme shape changes could redefine drug R&D approach
structural changes, which a catalytic enzyme undergoes in order to
carry out its biological function. The findings challenge
traditional hypothesis and may aid in future drug design.
Enzymes are biological molecules that accelerate chemical reactions and are central to the existence of life and these new findings are rewriting classical models of enzyme catalysis.
In addition, the new discovery questions current approaches used to rationally design enzyme inhibitors for the production of pharmaceuticals or novel enzyme catalysts for industrial applications.
Scientists from Scripps Research Department demonstrated that dynamic structural fluctuations channel an enzyme through its reaction cycle. The thermal motions of the protein are then harnessed to perform catalysis.
Using nuclear magnetic resonance (NMR), the researchers investigated higher energy excited states of E. coli dihydrofolate reductase (DHFR).
It was noticed that at each stage in the catalytic cycle, the excited-state conformations resembled the ground-state structures of both the preceding and the following intermediates.
Thus dynamic fluctuations between the ground state and the excited state were preparing the enzyme to take up the conformation of the adjacent intermediate state, facilitating the progress of catalysis by aiding the movement of ligands on and off the enzyme.
"There is a growing awareness that the inherent motions of proteins are essential to their functions," said Peter Wright, who is chair of the Scripps Research Department of Molecular Biology and a member of the Skaggs Institute for Chemical Biology at Scripps Research.
"These findings contrast with the traditional 'induced fit' hypothesis," Wright said. "One of the tenets of that hypothesis is that the binding of ligands induces a structural change that increases the complementary relationship between the ligand and the enzyme."
Over the years, drug design has been implemented with the assumption that the majority of many enzymes are inherently flexible. However, the fundamental mechanisms by which protein fluctuations couple with catalytic function remain poorly understood.
It is hoped that this new conformational model will add more insight into enzyme interactions leading to a more strategic approach to drug development.
"Our study can be placed in the broader context of the catalytic cycle," Wright said. "The results imply that for each of the intermediates in the catalytic cycle of DHFR, the lowest energy excited states are the most functionally relevant conformations."
"The enzyme structure responds to ligands by taking up a preferred ground-state conformation, but also samples other relevant conformations of higher energy, enabling it to rapidly advance to the next steps in catalysis. As ligands change, the energy landscape and the accessible states of the enzyme change in response. Consequently, this dynamic energy landscape efficiently funnels the enzyme along a specific kinetic path, where the number and heights of the barriers between consecutive conformations have been minimised," he added.
