3OX1

X-ray Structural study of quinone reductase II inhibition by compounds with micromolar to nanomolar range IC50 values

3OX1 の概要

• エントリーDOI: 10.2210/pdb3ox1/pdb
• 関連するPDBエントリー: 3OVM 3OWH 3OWX
• 分子名称: Ribosyldihydronicotinamide dehydrogenase [quinone], ZINC ION, FLAVIN-ADENINE DINUCLEOTIDE, ... (5 entities in total)
• 機能のキーワード: qr2, nq02, flavoprotein, metal-2 binding, oxidoreductase, phosphoprotein, fad
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P16083
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 54275.74

構造登録者

Pegan, S.D.,Sturdy, M.,Ferry, G.,Delagrange, P.,Boutin, J.A.,Mesecar, A.D. (登録日: 2010-09-21, 公開日: 2011-05-25, 最終更新日: 2024-02-21)

主引用文献

Pegan, S.D.,Sturdy, M.,Ferry, G.,Delagrange, P.,Boutin, J.A.,Mesecar, A.D.
X-ray structural studies of quinone reductase 2 nanomolar range inhibitors.
Protein Sci., 20:1182-1195, 2011

PubMed Abstract: Quinone reductase 2 (QR2) is one of two members comprising the mammalian quinone reductase family of enzymes responsible for performing FAD mediated reductions of quinone substrates. In contrast to quinone reductase 1 (QR1) which uses NAD(P)H as its co-substrate, QR2 utilizes a rare group of hydride donors, N-methyl or N-ribosyl nicotinamide. Several studies have linked QR2 to the generation of quinone free radicals, several neuronal degenerative diseases, and cancer. QR2 has been also identified as the third melatonin receptor (MT3) through in cellulo and in vitro inhibition of QR2 by traditional MT3 ligands, and through recent X-ray structures of human QR2 (hQR2) in complex with melatonin and 2-iodomelatonin. Several MT3 specific ligands have been developed that exhibit both potent in cellulo inhibition of hQR2 nanomolar, affinity for MT3. The potency of these ligands suggest their use as molecular probes for hQR2. However, no definitive correlation between traditionally obtained MT3 ligand affinity and hQR2 inhibition exists limiting our understanding of how these ligands are accommodated in the hQR2 active site. To obtain a clearer relationship between the structures of developed MT3 ligands and their inhibitory properties, in cellulo and in vitro IC₅₀ values were determined for a representative set of MT3 ligands (MCA-NAT, 2-I-MCANAT, prazosin, S26695, S32797, and S29434). Furthermore, X-ray structures for each of these ligands in complex with hQR2 were determined allowing for a structural evaluation of the binding modes of these ligands in relation to the potency of MT3 ligands.

PubMed: 21538647
DOI: 10.1002/pro.647

実験手法

X-RAY DIFFRACTION (2 Å)