4BTW

Crystal structure of human vascular adhesion protein-1 in complex with pyridazinone inhibitors

4BTW の概要

• エントリーDOI: 10.2210/pdb4btw/pdb
• 関連するPDBエントリー: 4BTX 4BTY
• 分子名称: MEMBRANE PRIMARY AMINE OXIDASE, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• 機能のキーワード: oxidoreductase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Membrane; Single-pass type II membrane protein: Q16853
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 168427.30

構造登録者

Bligt-Linden, E.,Pihlavisto, M.,Szatmari, I.,Otwinowski, Z.,Smith, D.J.,Lazar, L.,Fulop, F.,Salminen, T.A. (登録日: 2013-06-19, 公開日: 2013-12-18, 最終更新日: 2023-12-20)

主引用文献

Bligt-Linden, E.,Pihlavisto, M.,Szatmari, I.,Otwinowski, Z.,Smith, D.J.,Lazar, L.,Fulop, F.,Salminen, T.A.
Novel Pyridazinone Inhibitors for Vascular Adhesion Protein- 1 (Vap-1): Old Target - New Inhibition Mode.
J.Med.Chem., 56:9837-, 2013

PubMed Abstract: Vascular adhesion protein-1 (VAP-1) is a primary amine oxidase and a drug target for inflammatory and vascular diseases. Despite extensive attempts to develop potent, specific, and reversible inhibitors of its enzyme activity, the task has proven challenging. Here we report the synthesis, inhibitory activity, and molecular binding mode of novel pyridazinone inhibitors, which show specificity for VAP-1 over monoamine and diamine oxidases. The crystal structures of three inhibitor-VAP-1 complexes show that these compounds bind reversibly into a unique binding site in the active site channel. Although they are good inhibitors of human VAP-1, they do not inhibit rodent VAP-1 well. To investigate this further, we used homology modeling and structural comparison to identify amino acid differences, which explain the species-specific binding properties. Our results prove the potency and specificity of these new inhibitors, and the detailed characterization of their binding mode is of importance for further development of VAP-1 inhibitors.

PubMed: 24304424
DOI: 10.1021/JM401372D

実験手法

X-RAY DIFFRACTION (2.8 Å)