8RAK

Crystal structure of human Dihydroorotate Dehydrogenase in complex with the inhibitor 2-Hydroxy-N-(2-isopropyl-5-methyl-4-(pyridin-4-yloxy)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

8RAK の概要

• エントリーDOI: 10.2210/pdb8rak/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (7 entities in total)
• 機能のキーワード: drug discovery, dhodh, inhibitor, leukemia, protein binding, flavoprotein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44138.65

構造登録者

Alberti, M.,Miggiano, R. (登録日: 2023-12-01, 公開日: 2024-06-19)

主引用文献

Alberti, M.,Poli, G.,Broggini, L.,Sainas, S.,Rizzi, M.,Boschi, D.,Ferraris, D.M.,Martino, E.,Ricagno, S.,Tuccinardi, T.,Lolli, M.L.,Miggiano, R.
An alternative conformation of the N-terminal loop of human dihydroorotate dehydrogenase drives binding to a potent antiproliferative agent.
Acta Crystallogr D Struct Biol, 80:386-396, 2024

PubMed Abstract: 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/logD balance and identify membrane-permeable molecules with a drug-like profile in terms of water solubility.

PubMed: 38805244
DOI: 10.1107/S2059798324004066

実験手法

X-RAY DIFFRACTION (1.85 Å)