Reconciling the lock-and-key and dynamic views of canonical serine protease inhibitor action

• Published in: FEBS letters Vol. 584; no. 1; pp. 203 - 206
• Main Authors: Gáspári, Zoltán, Várnai, Péter, Szappanos, Balázs, Perczel, András
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 04.01.2010
• Subjects: Canonical serine protease inhibitor; Dynamic conformational ensemble; Internal dynamics; Molecular Dynamics Simulation; Nanosecond-timescale conformer selection; Population shift; Protease binding; Serine Proteases - chemistry; Serine Proteases - drug effects; Trypsin Inhibitors - pharmacology; Nanosecond-timescale conformer selection; Population shift; Dynamic conformational ensemble; Protease binding; Canonical serine protease inhibitor; Internal dynamics
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2009.11.058

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.