5KEZ

Selective and potent inhibition of the glycosidase human amylase by the short and extremely compact peptide piHA from mRNA display

Summary for 5KEZ

• Entry DOI: 10.2210/pdb5kez/pdb
• Related: 1CPU 4W93 4X9Y
• Descriptor: Pancreatic alpha-amylase, ACE-DTY-PRO-TYR-SER-CYS-TRP-VAL-ARG-HIS-NH2, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: amylase, diabetes, obesity, glucosyl hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted, extracellular space: P04746
• Total number of polymer chains: 2
• Total formula weight: 57243.26

Authors

Caner, S.,Brayer, G.D. (deposition date: 2016-06-10, release date: 2017-03-29, Last modification date: 2024-11-20)

Primary citation

Jongkees, S.A.,Caner, S.,Tysoe, C.,Brayer, G.D.,Withers, S.G.,Suga, H.
Rapid Discovery of Potent and Selective Glycosidase-Inhibiting De Novo Peptides.
Cell Chem Biol, 24:381-390, 2017

PubMed Abstract: Human pancreatic α-amylase (HPA) is responsible for degrading starch to malto-oligosaccharides, thence to glucose, and is therefore an attractive therapeutic target for the treatment of diabetes and obesity. Here we report the discovery of a unique lariat nonapeptide, by means of the RaPID (Random non-standard Peptides Integrated Discovery) system, composed of five amino acids in a head-to-side-chain thioether macrocycle and a further four amino acids in a 3 helical C terminus. This is a potent inhibitor of HPA (K = 7 nM) yet exhibits selectivity for the target over other glycosidases tested. Structural studies show that this nonapeptide forms a compact tertiary structure, and illustrate that a general inhibitory motif involving two phenolic groups is often accessed for tight binding of inhibitors to HPA. Furthermore, the work reported here demonstrates the potential of this methodology for the discovery of de novo peptide inhibitors against other glycosidases.

PubMed: 28262556
DOI: 10.1016/j.chembiol.2017.02.001

Experimental method

X-RAY DIFFRACTION (1.83 Å)