This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.It is unclear why the zinc aminopeptidase from Aeromonas proteolytica (AAP) has very large differences in the affinities for various inhibitors. Complex crystal structures show little to no movement of the atoms in the active site. AAP binds the tetrahedral inhibitor analogue- leucine phosphonic acid (LPA) with a thousand times higher affinity than the product leucine. Complex structures of both leucine phosphonic acid and product reveal nearly identical placement of the atoms in the dizinc active site. Both complex structures show the hydrophobic moiety situated nicely into the hydrophobic pocket with short oxygen-zinc coordination bonds. So why does the leucine phosphonic acid with a sp3 hybridized phosphate bind a thousand times greater than leucine with a sp2 hybridized carbon? Recent high resolution structures of conserved second shell mutant variant of AAP reveal an extraordinary finding- AAP may be using coordination strain of the zinc to mediate product release. The recently solved 1.2 Angstrom structure of the second shell S228A variant with a product in the active site has allowed us to propose a hypothesis as to why product binds the mutant enzyme almost twenty times better than WT. Loss of the short S228-D179 bond allows the active site to accommodate a trigonal bipyrimidal geometry (as opposed to octahedral seen with the WT-product complex) and this may represent a lower energy coordination for zinc2. We have other mutants that support our hypothesis of geometric strain playing a role in the reaction mechanism. We have crystals of WT and variants of AAP in complex with both LPA and leucine that require high resolution structure determination to accurately determine bond lengths, geometries, and angles. With kinetic and high resolution analysis of WT, S228A, M180A, D118A, D118N, and other variant we are on our way to uncovering the entatic nature of zinc enzymes and the use of geometric strain in the reaction mechanism.
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