4BFH
Crystal structure of alpha-amylase inhibitor wrightide R1 (wR1) peptide from Wrightia religiosa
Summary for 4BFH
| Entry DOI | 10.2210/pdb4bfh/pdb |
| Descriptor | WRIGHTIDE R1 (2 entities in total) |
| Functional Keywords | hydrolase inhibitor, insect alpha-amylase inhibitor |
| Biological source | WRIGHTIA RELIGIOSA |
| Total number of polymer chains | 1 |
| Total formula weight | 3255.76 |
| Authors | Yap, L.J.,Nguyen, P.Q.T.,Tam, J.P.,Lescar, J. (deposition date: 2013-03-19, release date: 2013-07-10, Last modification date: 2024-10-16) |
| 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-, 2014 Cited by 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: 25040200DOI: 10.1111/FEBS.12939 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.25 Å) |
Structure validation
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