ArticleProceedings of the National Academy of Sciences of the United States of America2018
Structures and mechanism of dipeptidyl peptidases 8 and 9, important players in cellular homeostasis and cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 82 citations in OpenAlex.
- Caspase-mediated cleavage events hidden by secondary proteolysis during apoptosis.Protein science : a publication of the Protein Society · 2026Article
- Disease-associated genetic variants can cause missense effects in tissue-specific protein isoforms.Nature communications · 2026Article
- Proximity labeling reveals non-catalytic interactions between DPP9 and ubiquitin signaling complexes.Cellular and molecular life sciences : CMLS · 2026Article
- The Caenorhabditis elegans DPF-3 and human DPP4 have tripeptidyl peptidase activity.FEBS letters · 2026Article
- Hippocampal dipeptidyl peptidase 9 bidirectionally regulates memory associated with synaptic plasticity.Journal of advanced research · 2025Article
- A fluorescent sensor for real-time monitoring of DPP8/9 reveals crucial roles in immunity and cancer.Life science alliance · 2025Article
- Macrocyclic Phage Display for Identification of Selective Protease Substrates.Journal of the American Chemical Society · 2025Article
- The multifunctional regulatory post-proline protease dipeptidyl peptidase 9 and its inhibitors: new opportunities for therapeutics.Cellular and molecular life sciences : CMLS · 2025Review
- Sulphostin-inspired N-phosphonopiperidones as selective covalent DPP8 and DPP9 inhibitors.Nature communications · 2025Article
- The serine protease DPP9 and the redox sensor KEAP1 form a mutually inhibitory complex.The Journal of biological chemistry · 2025Article
- Deep quantification of substrate turnover defines protease subsite cooperativity.Molecular systems biology · 2024Article
- Cosolvent Molecular Dynamics Applied to DPP4, DPP8 and DPP9: Reproduction of Important Binding Features and Use in Inhibitor Design.Journal of chemical information and modeling · 2024Article
- Hemophagocytic lymphohistiocytosis-like hyperinflammation due to a de novo mutation in DPP9.The Journal of allergy and clinical immunology · 2023Article
- Article
- Integrative bioinformatics analysis of biomarkers and pathways for exploring the mechanisms and molecular targets associated with pyroptosis in type 2 diabetes mellitus.Frontiers in endocrinology · 2023Article
- Suspected adverse drug reactions of the type 2 antidiabetic drug class dipeptidyl-peptidase IV inhibitors (DPP4i): Can polypharmacology help explain?Pharmacology research & perspectives · 2022Article
- Chemoproteomics-Enabled Identification of 4-Oxo-β-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9.Angewandte Chemie (International ed. in English) · 2022Article
- Dipeptidyl peptidase 9 triggers BRCA2 degradation and promotes DNA damage repair.EMBO reports · 2022Article
- Molecular design of near-infrared (NIR) fluorescent probes targeting exopeptidase and application for detection of dipeptidyl peptidase 4 (DPP-4) activity.RSC chemical biology · 2022Article
- A Surface Plasmon Resonance-Based Strategy to Characterize Interactions of NLR Proteins with Associated Factors.Methods in molecular biology (Clifton, N.J.) · 2022Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Dipeptidyl peptidases 8 and 9 are intracellular N-terminal dipeptidyl peptidases (preferentially postproline) associated with pathophysiological roles in immune response and cancer biology. While the DPP family member DPP4 is extensively characterized in molecular terms as a validated therapeutic target of type II diabetes, experimental 3D structures and ligand-/substrate-binding modes of DPP8 and DPP9 have not been reported. In this study we describe crystal and molecular structures of human DPP8 (2.5 Å) and DPP9 (3.0 Å) unliganded and complexed with a noncanonical substrate and a small molecule inhibitor, respectively. Similar to DPP4, DPP8 and DPP9 molecules consist of one β-propeller and α/β hydrolase domain, forming a functional homodimer. However, they differ extensively in the ligand binding site structure. In intriguing contrast to DPP4, where liganded and unliganded forms are closely similar, ligand binding to DPP8/9 induces an extensive rearrangement at the active site through a disorder-order transition of a 26-residue loop segment, which partially folds into an α-helix (R-helix), including R160/133, a key residue for substrate binding. As vestiges of this helix are also seen in one of the copies of the unliganded form, conformational selection may contributes to ligand binding. Molecular dynamics simulations support increased flexibility of the R-helix in the unliganded state. Consistently, enzyme kinetics assays reveal a cooperative allosteric mechanism. DPP8 and DPP9 are closely similar and display few opportunities for targeted ligand design. However, extensive differences from DPP4 provide multiple cues for specific inhibitor design and development of the DPP family members as therapeutic targets or antitargets.
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