COMPETITIVE BINDING OF POTENTIAL DRUG MOLECULES AT THE ACTIVE SITE OF AN ACYLPEPTIDE-HYDROLASE

For members of its enzyme family two basic ways of substrate selection have been discovered: flexible domain movement between opened and closed form, or multimerization of rigid monomers. The formation of multimers is linked to the shielding of the "sticky edge" of a -sheet to avoid aggregation. In archeal PhAAP formation of hexamers with a complex channel system is responsible for -edge shielding and for the size selection too, in contrast, Aeropyrum pernix AAP (ApAAP) forms dimers capable for a gating mechanism by domain movements providing size selection of the substrates [1]. The mammalian enzyme – present also in the human liver – is a key protein in the upstream regulation of the proteasome [2]. It was also proven to be part of a competitive binding process with a carbapenem type of antibiotics, such as meropenem [3]. The goal of our study is to determine the process of this competition with the help of protein crystallography on the archaeal analogues, since the structure of the mammalian AAP has not yet been determined.