3ZWS

Structure of Human Dihydroorotate Dehydrogenase with a Bound Inhibitor

3ZWS の概要

• エントリーDOI: 10.2210/pdb3zws/pdb
• 関連するPDBエントリー: 1D3G 1D3H 2B0M 2BXV 2WV8 3ZWT
• 分子名称: DIHYDROOROTATE DEHYDROGENASE (QUINONE), MITOCHONDRIAL, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (8 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: Mitochondrion inner membrane; Single-pass membrane protein: Q02127
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41155.86

構造登録者

Acklam, P.A.,Parsons, M.R. (登録日: 2011-08-02, 公開日: 2012-06-27, 最終更新日: 2024-05-08)

主引用文献

Bedingfield, P.T.P.,Cowen, D.,Acklam, P.A.,Cunningham, F.,Parsons, M.R.,Mcconkey, G.A.,Fishwick, C.W.G.,Johnson, A.P.
Factors Influencing the Specificity of Inhibitor Binding to the Human and Malaria Parasite Dihydroorotate Dehydrogenases.
J.Med.Chem., 55:5841-, 2012

PubMed Abstract: The de novo pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase is an emerging drug target for the treatment of malaria. In this context a key property of Plasmodium falciparum DHODH (PfDHODH) is that it can be selectively inhibited over its human homologue (HsDHODH). However, HsDHODH is also a validated drug target for autoimmune diseases such as arthritis. Here a series of novel inhibitors is described that includes compounds that switch specificity between the two enzymes as a result of small alterations in chemical structure. Structure-activity relationship (SAR), crystallography, docking, and mutagenesis studies are used to examine the binding modes of the compounds within the two enzymes and to reveal structural changes induced by inhibitor binding. Within this series, compounds with therapeutically relevant HsDHODH activity are described and their binding modes characterized using X-ray crystallography, which reveals a novel conformational shift within the inhibitor binding site.

PubMed: 22621375
DOI: 10.1021/JM300157N

実験手法

X-RAY DIFFRACTION (1.6 Å)