2MAU

Solution structure of alpha-amylase inhibitor wrightide R1 (wR1) peptide from Wrightia religiosa

Summary for 2MAU

• Entry DOI: 10.2210/pdb2mau/pdb
• NMR Information: BMRB: 19374
• Descriptor: Wrightide R1 (1 entity in total)
• Functional Keywords: cystine knot, alpha amylase inhibitor, hydrolase inhibitor
• Biological source: Wrightia religiosa
• Total number of polymer chains: 1
• Total formula weight: 3255.76

Authors

Wang, S.,Nguyen, Q.,Tam, J. (deposition date: 2013-07-17, release date: 2014-07-23, Last modification date: 2024-11-06)

Primary citation

Nguyen, P.Q.,Wang, S.,Kumar, A.,Yap, L.J.,Luu, T.T.,Lescar, J.,Tam, J.P.
Discovery and characterization of pseudocyclic cystine-knot alpha-amylase inhibitors with high resistance to heat and proteolytic degradation.
Febs J., 281:4351-4366, 2014

PubMed Abstract: Obesity and type 2 diabetes are chronic metabolic diseases, and those affected could benefit from the use of α-amylase inhibitors to manage starch intake. The pseudocyclics, wrightides Wr-AI1 to Wr-AI3, isolated from an Apocynaceae plant show promise for further development as orally active α-amylase inhibitors. These linear peptides retain the stability known for cystine-knot peptides in the presence of harsh treatment. They are resistant to heat treatment and endopeptidase and exopeptidase degradation, which is characteristic of cyclic cystine-knot peptides. Our NMR and crystallography analysis also showed that wrightides, which are currently the smallest proteinaceous α-amylase inhibitors reported, contain the backbone-twisting cis-proline, which is preceded by a nonaromatic residue rather than a conventional aromatic residue. The modeled structure and a molecular dynamics study of Wr-AI1 in complex with yellow mealworm α-amylase suggested that, despite having a similar structure and cystine-knot fold, the knottin-type α-amylase inhibitors may bind to insect α-amylase via a different set of interactions. Finally, we showed that the precursors of pseudocyclic cystine-knot α-amylase inhibitors and their biosynthesis in plants follow a secretory protein synthesis pathway. Together, our findings provide insights for the use of the pseudocyclic α-amylase inhibitors as useful leads for the development of orally active peptidyl bioactives, as well as an alternative scaffold for cyclic peptides for engineering metabolically stable human α-amylase inhibitors.

PubMed: 25040200
DOI: 10.1111/febs.12939

Experimental method

SOLUTION NMR