{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T22:42:07Z","timestamp":1768257727467,"version":"3.49.0"},"reference-count":50,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T00:00:00Z","timestamp":1722211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glutaminyl-peptide cyclotransferases (QCs) convert the N-terminal glutamine or glutamate residues of protein and peptide substrates into pyroglutamate (pE) by releasing ammonia or a water molecule. The N-terminal pE modification protects peptides\/proteins against proteolytic degradation by amino- or exopeptidases, increasing their stability. Mammalian QC is abundant in the brain and a large amount of evidence indicates that pE peptides are involved in the onset of neural human pathologies such as Alzheimer\u2019s and Huntington\u2019s disease and synucleinopathies. Hence, human QC (hQC) has become an intensively studied target for drug development against these diseases. Soon after its characterization, hQC was identified as a Zn-dependent enzyme, but a partial restoration of the enzyme activity in the presence of the Co(II) ion was also reported, suggesting a possible role of this metal ion in catalysis. The present work aims to investigate the structure of demetallated hQC and of the reconstituted enzyme with Zn(II) and Co(II) and their behavior in the presence of known inhibitors. Furthermore, our structural determinations provide a possible explanation for the presence of the mononuclear metal binding site of hQC, despite the presence of the same conserved metal binding motifs present in distantly related dinuclear aminopeptidase enzymes.<\/jats:p>","DOI":"10.3390\/ijms25158279","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T17:08:34Z","timestamp":1722359314000},"page":"8279","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Metal Ion Binding to Human Glutaminyl Cyclase: A Structural Perspective"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-5528","authenticated-orcid":false,"given":"Giusy","family":"Tassone","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018\u20132022, University of Siena, Via Aldo Moro 2, I-53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2574-3911","authenticated-orcid":false,"given":"Cecilia","family":"Pozzi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018\u20132022, University of Siena, Via Aldo Moro 2, I-53100 Siena, Italy"},{"name":"Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (CIRMMP), Via Luigi Sacconi 6, I-50019 Sesto Fiorentino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4824-7478","authenticated-orcid":false,"given":"Stefano","family":"Mangani","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018\u20132022, University of Siena, Via Aldo Moro 2, I-53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13415","DOI":"10.1021\/bi051142e","article-title":"Isolation, Catalytic Properties, and Competitive Inhibitors of the Zinc-Dependent Murine Glutaminyl Cyclase","volume":"44","author":"Schilling","year":"2005","journal-title":"Biochemistry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11831","DOI":"10.1021\/bi9018835","article-title":"Glutaminyl Cyclases Display Significant Catalytic Proficiency for Glutamyl Substrates","volume":"48","author":"Seifert","year":"2009","journal-title":"Biochemistry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"103644","DOI":"10.1016\/j.drudis.2023.103644","article-title":"Therapeutic Potential of Glutaminyl Cyclases: Current Status and Emerging Trends","volume":"28","author":"Coimbra","year":"2023","journal-title":"Drug Discov. 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