دورية أكاديمية
An alternative conformation of the N-terminal loop of human dihydroorotate dehydrogenase drives binding to a potent antiproliferative agent.
| العنوان: | An alternative conformation of the N-terminal loop of human dihydroorotate dehydrogenase drives binding to a potent antiproliferative agent. |
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| المؤلفون: | Alberti M; Department of Pharmaceutical Sciences, University of Piemonte Orientale, Via G. Bovio 6, 28100 Novara, Italy., Poli G; Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy., Broggini L; Institute of Molecular and Translational Cardiology, IRCCS Policlinico San Donato, Piazza Malan, 20097 San Donato Milanese, Italy., Sainas S; Department of Sciences and Drug Technology, University of Torino, Via P. Giuria 9, 10125 Torino, Italy., Rizzi M; Department of Pharmaceutical Sciences, University of Piemonte Orientale, Via G. Bovio 6, 28100 Novara, Italy., Boschi D; Department of Sciences and Drug Technology, University of Torino, Via P. Giuria 9, 10125 Torino, Italy., Ferraris DM; Department of Pharmaceutical Sciences, University of Piemonte Orientale, Via G. Bovio 6, 28100 Novara, Italy., Martino E; Department of Sciences and Drug Technology, University of Torino, Via P. Giuria 9, 10125 Torino, Italy., Ricagno S; Institute of Molecular and Translational Cardiology, IRCCS Policlinico San Donato, Piazza Malan, 20097 San Donato Milanese, Italy., Tuccinardi T; Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy., Lolli ML; Department of Sciences and Drug Technology, University of Torino, Via P. Giuria 9, 10125 Torino, Italy., Miggiano R; Department of Pharmaceutical Sciences, University of Piemonte Orientale, Via G. Bovio 6, 28100 Novara, Italy. |
| المصدر: | Acta crystallographica. Section D, Structural biology [Acta Crystallogr D Struct Biol] 2024 Jun 01; Vol. 80 (Pt 6), pp. 386-396. Date of Electronic Publication: 2024 May 28. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: John Wiley & Sons Country of Publication: United States NLM ID: 101676043 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2059-7983 (Electronic) Linking ISSN: 20597983 NLM ISO Abbreviation: Acta Crystallogr D Struct Biol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: <2018-> : Medford, MA : John Wiley & Sons Original Publication: [Malden, MA] : John Wiley & Sons, [2016]- |
| مواضيع طبية MeSH: | Dihydroorotate Dehydrogenase* , Oxidoreductases Acting on CH-CH Group Donors*/chemistry , Oxidoreductases Acting on CH-CH Group Donors*/antagonists & inhibitors , Oxidoreductases Acting on CH-CH Group Donors*/metabolism, Humans ; Crystallography, X-Ray/methods ; Binding Sites ; Pyridines/chemistry ; Pyridines/pharmacology ; Protein Conformation ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Models, Molecular ; Protein Binding ; Hydrogen Bonding |
| مستخلص: | Over the years, human dihydroorotate dehydrogenase (hDHODH), which is a key player in the de novo pyrimidine-biosynthesis pathway, has been targeted in the treatment of several conditions, including autoimmune disorders and acute myelogenous leukaemia, as well as in host-targeted antiviral therapy. A molecular exploration of its inhibitor-binding behaviours yielded promising candidates for innovative drug design. A detailed description of the enzymatic pharmacophore drove the decoration of well-established inhibitory scaffolds, thus gaining further in vitro and in vivo efficacy. In the present work, using X-ray crystallography, an atypical rearrangement was identified in the binding pose of a potent inhibitor characterized by a polar pyridine-based moiety (compound 18). The crystal structure shows that upon binding compound 18 the dynamics of a protein loop involved in a gating mechanism at the cofactor-binding site is modulated by the presence of three water molecules, thus fine-tuning the polarity/hydrophobicity of the binding pocket. These solvent molecules are engaged in the formation of a hydrogen-bond mesh in which one of them establishes a direct contact with the pyridine moiety of compound 18, thus paving the way for a reappraisal of the inhibition of hDHODH. Using an integrated approach, the thermodynamics of such a modulation is described by means of isothermal titration calorimetry coupled with molecular modelling. These structural insights will guide future drug design to obtain a finer K |
| معلومات مُعتمدة: | DSF-FAR 2017 Ministero dell'Università e della Ricerca; LOLM_S1921_EX-POST_21_01 Ministero dell'Università e della Ricerca; LOLM_SPS_NATO_22_01 Ministero dell'Università e della Ricerca |
| فهرسة مساهمة: | Keywords: DHODH; X-ray crystallography; human dihydroorotate dehydrogenase; pyrimidine biosynthesis; structure-based drug discovery |
| المشرفين على المادة: | 0 (Dihydroorotate Dehydrogenase) EC 1.3.- (Oxidoreductases Acting on CH-CH Group Donors) 0 (Pyridines) 0 (Enzyme Inhibitors) |
| تواريخ الأحداث: | Date Created: 20240528 Date Completed: 20240606 Latest Revision: 20240614 |
| رمز التحديث: | 20240614 |
| DOI: | 10.1107/S2059798324004066 |
| PMID: | 38805244 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2059-7983 |
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| DOI: | 10.1107/S2059798324004066 |