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Allosteric Inhibitor of ERAP1 Acts by Stabilizing a Closed Conformation
Author(s) -
Maben Zachary,
Arya Richa,
Stern Lawrence
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.527.11
Subject(s) - allosteric regulation , chemistry , small angle x ray scattering , stereochemistry , dipeptide , aminopeptidase , peptide , enzyme , biochemistry , leucine , amino acid , physics , scattering , optics
Endoplasmic‐reticulum associated aminopeptidase 1 (ERAP1) is a M1 family zinc aminopeptidase that generates peptides for class I major histocompatibility complex (MHC‐I) presentation and T cell surveillance. ERAP1 has been crystalized in open and closed states, and is postulated to convert between them during its catalytic cycle. Small‐angle X‐ray scattering (SAXS) studies show that in solution ERAP1 predominately adopts the open conformation. A highly specific small‐molecule inhibitor of ERAP1 causes it to adopt a closed conformation, suggesting an allosteric inhibition mechanism. The compound inhibits ERAP1 peptide processing activity but activates hydrolysis activity of a dipeptide analog, leucine‐7‐amido‐4‐methylcoumarin, supporting an allosteric mechanism. The inhibitor also differentially alters enzymatic behavior of naturally occurring ERAP1 variants with lysine or arginine at position 528, which differ in their solution conformational equilbrium. Arg/Lys 528 forms an electrostatic interaction in the closed conformation that is broken when ERAP1 adopts the open conformation; computational studies predict that substitution of arginine for lysine decreases the electrostatic potential by 1.67 kT/e. We propose that this polymorphism alters the stability of the closed conformation, and that the differential behavior of the inhibitor for the ERAP1 variants is directly related to the stability of the closed conformation. The role of conformation in the catalytic cycle may be a feature of the entire M1 aminopeptidase family. Support or Funding Information This research was supported by NIH National Institute of Allergy and Infectious Diseases (NIAID) under the National Institutes of Health award number R01AI038996. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .