Structural basis for functional selectivity and ligand recognition revealed by crystal structures of human secreted...

Secreted phospholipases A₂s (sPLA₂s) are involved in various pathological conditions such as rheumatoid arthritis and cardiovascular disease. Many inhibitors were developed and studied in clinical trials, but none have reached the market yet. This failure may be attributed to the lack of subtype selectivity for these inhibitors. Therefore, more structural information for subtype sPLA₂ is needed to guide the selective inhibitor development. In this study, the crystal structure of human sPLA₂ Group IIE (hGIIE), coupled with mutagenesis experiments, proved that the flexible second calcium binding site and residue Asn21 in hGIIE are essential to its enzymatic activity. Five inhibitor bound hGIIE complex structures revealed the key residues (Asn21 and Gly6) of hGIIE that are responsible for interacting with inhibitors, and illustrated the difference in the inhibitor binding pocket with other sPLA₂s. This will facilitate the structure-based design of sPLA₂'s selective inhibitors.