8cgw | pdb_00008cgw
Insulin-regulated aminopeptidase (IRAP) in complex with an allosteric benzopyran-based inhibitor
Structural highlights
FunctionLCAP_HUMAN Release of an N-terminal amino acid, cleaves before cysteine, leucine as well as other amino acids. Degrades peptide hormones such as oxytocin, vasopressin and angiotensin III, and plays a role in maintaining homeostasis during pregnancy. May be involved in the inactivation of neuronal peptides in the brain. Cleaves Met-enkephalin and dynorphin. Binds angiotensin IV and may be the angiotensin IV receptor in the brain.[1] [2] [3] Publication Abstract from PubMedInhibition 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. Mechanisms of Allosteric Inhibition of Insulin-Regulated Aminopeptidase.,Mpakali A, Barla I, Lu L, Ramesh KM, Thomaidis N, Stern LJ, Giastas P, Stratikos E J Mol Biol. 2024 Jan 18;436(6):168449. doi: 10.1016/j.jmb.2024.168449. PMID:38244767[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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