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Ligand-induced conformational change of Insulin-regulated aminopeptidase: insights on catalytic mechanism and active site plasticity

DOI: 10.1021/acs.jmedchem.6b01890 DOI Help

Authors: Anastasia Mpakali (National Center for Scientific Research Demokritos) , Emmanuel Saridakis (National Center for Scientific Research Demokritos) , Karl Harlos (Wellcome Trust Centre for Human Genetics, Oxford University) , Yuguang Zhao (Wellcome Trust Centre for Human Genetics, Oxford University) , Paraskevi Kokkala (University of Athens) , Dimitris Georgiadis (University of Athens) , Petros Giastas (Hellenic Pasteur Institute) , Athanasios Papakyriakou (National Center for Scientific Research Demokritos) , Efstratios Stratikos (National Center for Scientific Research Demokritos)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: March 2017
Diamond Proposal Number(s): 10627

Abstract: Insulin-regulated aminopeptidase (IRAP) is an enzyme with several important biological functions that is known to process a large variety of different peptidic substrates although the mechanism behind this wide specificity is not clearly understood. We describe a crystal structure of IRAP in complex with a recently developed bioactive and selective inhibitor at 2.53 Å resolution. In the presence of this inhibitor the enzyme adopts a novel conformation in which domains II and IV are juxtaposed, forming a hollow structure that excludes external solvent access to the catalytic center. A loop adjacent to the enzyme’s GAMEN motif undergoes structural reconfiguration, allowing the accommodation of bulky inhibitor side-chains. Atomic interactions between the inhibitor and IRAP that are unique to this conformation can explain the strong selectivity compared to homologous aminopeptidases ERAP1 and ERAP2. This conformation provides insight on IRAP’s catalytic cycle and reveals significant active site plasticity that may underlie its substrate permissiveness.

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I03-Macromolecular Crystallography

Added On: 03/04/2017 11:40

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