ArticleBiochemistry2017
Critical Role of Interdomain Interactions in the Conformational Change and Catalytic Mechanism of Endoplasmic Reticulum Aminopeptidase 1.
Article in Biochemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Methods and Guidelines for Analyzing the Conformational Dynamics of Proteins in the Antigen Presentation Pathway.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Expression, Purification, and Functional Analysis Methods of Antigen-Processing Aminopeptidases ERAP1, ERAP2, and IRAP.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Discovery of Novel Allosteric Inhibitor Hits for Insulin-Regulated Aminopeptidase Provides Insights on Enzymatic Mechanism.ACS omega · 2025Article
- Stabilization of the open conformation οf insulin-regulated aminopeptidase by a novel substrate-selective small-molecule inhibitor.Protein science : a publication of the Protein Society · 2024Article
- ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights.Journal of medicinal chemistry · 2024Review
- Conflicting Interfacial Electrostatic Interactions as a Design Principle to Modulate Long-Range Interdomain Communication.ACS bio & med chem Au · 2024Article
- Structure-guided discovery of aminopeptidase ERAP1 variants capable of processing antigens with novel PC anchor specificities.Immunology · 2024Article
- ERAP2 Inhibition Induces Cell-Surface Presentation by MOLT-4 Leukemia Cancer Cells of Many Novel and Potentially Antigenic Peptides.International journal of molecular sciences · 2022Article
- Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism.Nature communications · 2021Article
- The ERAP1 active site cannot productively access the N-terminus of antigenic peptide precursors stably bound onto MHC class I.Scientific reports · 2021Article
- Discovery of Selective Inhibitor Leads by Targeting an Allosteric Site in Insulin-Regulated Aminopeptidase.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Structural Basis of Inhibition of Insulin-Regulated Aminopeptidase by a Macrocyclic Peptidic Inhibitor.ACS medicinal chemistry letters · 2020Article
- A systematic re-examination of processing of MHCI-bound antigenic peptide precursors by endoplasmic reticulum aminopeptidase 1.The Journal of biological chemistry · 2020Article
- Discovery of Selective Inhibitors of Endoplasmic Reticulum Aminopeptidase 1.Journal of medicinal chemistry · 2020Article
- Molecular pathways for antigenic peptide generation by ER aminopeptidase 1.Molecular immunology · 2019Review
- High-Resolution Crystal Structure of Endoplasmic Reticulum Aminopeptidase 1 with Bound Phosphinic Transition-State Analogue Inhibitor.ACS medicinal chemistry letters · 2019Article
- Aminobenzosuberone Scaffold as a Modular Chemical Tool for the Inhibition of Therapeutically Relevant M1 Aminopeptidases.Molecules (Basel, Switzerland) · 2018Article
- The partial dissociation of MHC class I-bound peptides exposes their N terminus to trimming by endoplasmic reticulum aminopeptidase 1.The Journal of biological chemistry · 2018Article
- Caspase-9 CARD : core domain interactions require a properly formed active site.The Biochemical journal · 2018Article
- The Role of Molecular Flexibility in Antigen Presentation and T Cell Receptor-Mediated Signaling.Frontiers in immunology · 2018Review
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an intracellular enzyme that is important for the generation of antigenic epitopes and major histocompatibility class I-restricted adaptive immune responses. ERAP1 processes a vast variety of different peptides but still shows length and sequence selectivity, although the mechanism behind these properties is poorly understood. X-ray crystallographic analysis has revealed that ERAP1 can assume at least two distinct conformations in which C-terminal domain IV is either proximal or distal to active site domain II. To improve our understanding of the role of this conformational change in the catalytic mechanism of ERAP1, we used site-directed mutagenesis to perturb key salt bridges between domains II and IV. Enzymatic analysis revealed that these mutations, although located away from the catalytic site, greatly reduce the catalytic efficiency and change the allosteric kinetic behavior. The variants were more efficiently activated by small peptides and bound a competitive inhibitor with weaker affinity and faster dissociation kinetics. Molecular dynamics analysis suggested that the mutations affect the conformational distribution of ERAP1, reducing the population of closed states. Small-angle X-ray scattering indicated that both the wild type and the ERAP1 variants are predominantly in an open conformational state in solution. Overall, our findings suggest that electrostatic interactions between domains II and IV in ERAP1 are crucial for driving a conformational change that regulates the structural integrity of the catalytic site. The extent of domain opening in ERAP1 probably underlies its specialization for antigenic peptide precursors and should be taken into account in inhibitor development efforts.
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