2. Academic Validation
  3. Structural basis for functional selectivity and ligand recognition revealed by crystal structures of human secreted phospholipase A2 group IIE

Structural basis for functional selectivity and ligand recognition revealed by crystal structures of human secreted phospholipase A2 group IIE

  • Sci Rep. 2017 Sep 7;7(1):10815. doi: 10.1038/s41598-017-11219-8.
Shulin Hou 1 2,  Tingting Xu 1 3,  Jinxin Xu 1,  Linbing Qu 1,  Yong Xu 4,  Ling Chen 1,  Jinsong Liu 5 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100000, China.
  • 3 School of Life Sciences, University of Science and Technology of China, Hefei, 230026, China.
  • 4 Guangdong Provincial Key Laboratory of Biocomputing, Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
  • 5 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. liu_jinsong@gibh.ac.cn.
  • 6 Guangdong Provincial Key Laboratory of Biocomputing, Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. liu_jinsong@gibh.ac.cn.
PMID: 28883454 DOI: 10.1038/s41598-017-11219-8
Abstract

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.

Figures