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Reconciling the lock-and-key and dynamic views of canonical serine protease inhibitor action |
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| Authors: | Zoltá n Gá spá ri,Pé ter Vá rnai,Andrá s Perczel |
| Affiliation: | a Structural Chemistry and Biology Laboratory, Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary b Department of Chemistry and Biochemistry, University of Sussex, Brighton, UK c HAS-ELTE Protein Modelling Group, Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary |
| Abstract: | 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. |
| Keywords: | Canonical serine protease inhibitor Nanosecond-timescale conformer selection Protease binding Internal dynamics Dynamic conformational ensemble Population shift |
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