5VA9

Human pancreatic alpha amylase in complex with peptide inhibitor piHA-L5(d10Y)

5VA9 の概要

• エントリーDOI: 10.2210/pdb5va9/pdb
• 関連するPDBエントリー: 4W93 4X9Y 5E0F 5KEZ
• 分子名称: Pancreatic alpha-amylase, Peptide Inhibitor piHA-L5(d10Y), CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: amylase, diabetes, obesity, glucosyl hydrolase, peptide inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 116336.44

構造登録者

Caner, S.,Brayer, G.D. (登録日: 2017-03-24, 公開日: 2018-03-28, 最終更新日: 2024-11-06)

主引用文献

Goldbach, L.,Vermeulen, B.J.A.,Caner, S.,Liu, M.,Tysoe, C.,van Gijzel, L.,Yoshisada, R.,Trellet, M.,van Ingen, H.,Brayer, G.D.,Bonvin, A.M.J.J.,Jongkees, S.A.K.
Folding Then Binding vs Folding Through Binding in Macrocyclic Peptide Inhibitors of Human Pancreatic alpha-Amylase.
Acs Chem.Biol., 14:1751-1759, 2019

PubMed Abstract: macrocyclic peptides, derived using selection technologies such as phage and mRNA display, present unique and unexpected solutions to challenging biological problems. This is due in part to their unusual folds, which are able to present side chains in ways not available to canonical structures such as α-helices and β-sheets. Despite much recent interest in these molecules, their folding and binding behavior remains poorly characterized. In this work, we present cocrystallization, docking, and solution NMR structures of three macrocyclic peptides that all bind as competitive inhibitors with single-digit nanomolar to the active site of human pancreatic α-amylase. We show that a short stably folded motif in one of these is nucleated by internal hydrophobic interactions in an otherwise dynamic conformation in solution. Comparison of the solution structures with a target-bound structure from docking indicates that stabilization of the bound conformation is provided through interactions with the target protein after binding. These three structures also reveal a surprising functional convergence to present a motif of a single arginine sandwiched between two aromatic residues in the interactions of the peptide with the key catalytic residues of the enzyme, despite little to no other structural homology. Our results suggest that intramolecular hydrophobic interactions are important for priming binding of small macrocyclic peptides to their target and that high rigidity is not necessary for high affinity.

PubMed: 31241898
DOI: 10.1021/acschembio.9b00290

実験手法

X-RAY DIFFRACTION (2.55 Å)