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Download fileStructural Basis of Inhibition of Insulin-Regulated Aminopeptidase by a Macrocyclic Peptidic Inhibitor
journal contribution
posted on 2020-06-05, 12:07 authored by Anastasia Mpakali, Emmanuel Saridakis, Petros Giastas, Zachary Maben, Lawrence J. Stern, Mats Larhed, Mathias Hallberg, Efstratios StratikosInsulin-regulated
aminopeptidase (IRAP) is a transmembrane zinc
metallopeptidase with many important biological functions and an emerging
pharmacological target. Although previous structural studies have
given insight on how IRAP recognizes linear peptides, how it recognizes
its physiological cyclic ligands remains elusive. Here, we report
the first crystal structure of IRAP with the macrocyclic peptide inhibitor
HA08 that combines structural elements from angiotensin IV and the
physiological substrates oxytocin and vasopressin. The compound is
found in the catalytic site in a near canonical substrate-like configuration
and inhibits by a competitive mechanism. Comparison with previously
solved structures of IRAP along with small-angle X-ray scattering
experiments suggests that IRAP is in an open conformation in solution
but undergoes a closing conformational change upon inhibitor binding.
Stabilization of the closed conformation in combination with catalytic
water exclusion by the tightly juxtaposed GAMEN loop is proposed as
a mechanism of inhibition.
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Keywords
crystal structurewater exclusionInsulin-Regulated Aminopeptidasemechanismsubstrates oxytocinStructural Basisinhibitor bindingGAMEN loopconformationmacrocyclic peptide inhibitor HA 08small-angle X-rayIRAPangiotensin IVcanonical substrate-like configurationtransmembrane zinc metallopeptidasecyclic ligandsMacrocyclic Peptidic Inhibitor Insulin-regulated aminopeptidase