Reconciling the lock-and-key and dynamic views of canonical serine protease inhibitor action.
The efficiency of canonical serine protease inhibitors is conventionally attributed to the rigidity of their protease binding loop with no conformational change upon enzyme binding, yielding an example of the lock-and-key model for biomolecular interactions. However, solution-state structural studies revealed considerable flexibility in their protease binding loop. We resolve this apparent contradiction by showing that enzyme binding of small, 35-residue inhibitors is actually a dynamic conformer selection process on the nanosecond-timescale. Thus, fast timescale dynamics enables the association rate to be solely diffusion-controlled just like in the rigid-body model.
Gáspári
Zoltán
Z
Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary. szpari@chem.elte.hu
Várnai
Péter
P
Szappanos
Balázs
B
Perczel
András
A
D056004:Molecular Dynamics Simulation; D057057:Serine Proteases / Q000737:chemistry* / Q000187:drug effects*; D014361:Trypsin Inhibitors / Q000494:pharmacology*
D014361:Trypsin Inhibitors; D057057:Serine Proteases