8CGP
Insulin regulated aminopeptidase (IRAP) in complex with an allosteric aryl sulfonamide inhibitor
Summary for 8CGP
| Entry DOI | 10.2210/pdb8cgp/pdb |
| Descriptor | Leucyl-cystinyl aminopeptidase, pregnancy serum form, D-MALATE, ZINC ION, ... (15 entities in total) |
| Functional Keywords | insulin-regulated aminopeptidase, allosteric inhibitor, aryl sulfonamides, antigen presentation, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 215838.61 |
| Authors | Mpakali, A.,Stratikos, E.,Giastas, P. (deposition date: 2023-02-06, release date: 2024-01-31, Last modification date: 2024-11-20) |
| Primary citation | 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 Cited by 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: 38244767DOI: 10.1016/j.jmb.2024.168449 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.62 Å) |
Structure validation
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