8CGP

Insulin regulated aminopeptidase (IRAP) in complex with an allosteric aryl sulfonamide inhibitor

8CGP の概要

• エントリーDOI: 10.2210/pdb8cgp/pdb
• 分子名称: Leucyl-cystinyl aminopeptidase, pregnancy serum form, D-MALATE, ZINC ION, ... (15 entities in total)
• 機能のキーワード: insulin-regulated aminopeptidase, allosteric inhibitor, aryl sulfonamides, antigen presentation, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 215838.61

構造登録者

Mpakali, A.,Stratikos, E.,Giastas, P. (登録日: 2023-02-06, 公開日: 2024-01-31, 最終更新日: 2024-11-20)

主引用文献

Mpakali, A.,Barla, I.,Lu, L.,Ramesh, K.M.,Thomaidis, N.,Stern, L.J.,Giastas, P.,Stratikos, E.
Mechanisms of Allosteric Inhibition of Insulin-Regulated Aminopeptidase.
J.Mol.Biol., 436:168449-168449, 2024

PubMed Abstract: Inhibition of Insulin-Regulated Aminopeptidase is being actively explored for the treatment of several human diseases and several classes of inhibitors have been developed although no clinical applications have been reported yet. Here, we combine enzymological analysis with x-ray crystallography to investigate the mechanism employed by two of the most studied inhibitors of IRAP, an aryl sulfonamide and a 2-amino-4H-benzopyran named HFI-419. Although both compounds have been hypothesized to target the enzyme's active site by competitive mechanisms, we discovered that they instead target previously unidentified proximal allosteric sites and utilize non-competitive inhibition mechanisms. X-ray crystallographic analysis demonstrated that the aryl sulfonamide stabilizes the closed, more active, conformation of the enzyme whereas HFI-419 locks the enzyme in a semi-open, and likely less active, conformation. HFI-419 potency is substrate-dependent and fails to effectively block the degradation of the physiological substrate cyclic peptide oxytocin. Our findings demonstrate alternative mechanisms for inhibiting IRAP through allosteric sites and conformational restricting and suggest that the pharmacology of HFI-419 may be more complicated than initially considered. Such conformation-specific interactions between IRAP and small molecules can be exploited for the design of more effective second-generation allosteric inhibitors.

PubMed: 38244767
DOI: 10.1016/j.jmb.2024.168449

実験手法

X-RAY DIFFRACTION (2.62 Å)