posted on 2018-11-29, 00:00authored byIan W. Windsor, Brian Gold, Ronald T. Raines
Aspartic proteases
regulate many biological processes and are prominent
targets for therapeutic intervention. Structural studies have captured
intermediates along the reaction pathway, including the Michaelis
complex and tetrahedral intermediate. Using a Ramachandran analysis
of these structures, we discovered that residues occupying the P1
and P1′ positions (which flank the scissile peptide bond) adopt
the dihedral angle of an inverse γ-turn and polyproline type-II
helix, respectively. Computational analyses reveal that the polyproline
type-II helix engenders an n→π* interaction
in which the oxygen of the scissile peptide bond is the donor. This
interaction stabilizes the negative charge that develops in the tetrahedral
intermediate, much like the oxyanion hole of serine proteases. The
inverse γ-turn serves to twist the scissile peptide bond, vacating
the carbonyl π* orbital and facilitating its hydration. These
previously unappreciated interactions entail a form of substrate-assisted
catalysis and offer opportunities for drug design.