2G71

Structure of hPNMT with inhibitor 3-fluoromethyl-7-trifluoropropyl-THIQ and AdoHcy

2G71 の概要

• エントリーDOI: 10.2210/pdb2g71/pdb
• 関連するPDBエントリー: 1HNN 1N7I 1N7J 1YZ3 2g70 2g72
• 分子名称: Phenylethanolamine N-methyltransferase, S-ADENOSYL-L-HOMOCYSTEINE, (3R)-3-(FLUOROMETHYL)-N-(3,3,3-TRIFLUOROPROPYL)-1,2,3,4-TETRAHYDROISOQUINOLINE-7-SULFONAMIDE, ... (5 entities in total)
• 機能のキーワード: methyltransferase, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65233.52

構造登録者

Tyndall, J.D.A.,Gee, C.L.,Martin, J.L. (登録日: 2006-02-27, 公開日: 2007-02-13, 最終更新日: 2024-10-30)

主引用文献

Gee, C.L.,Drinkwater, N.,Tyndall, J.D.A.,Grunewald, G.L.,Wu, Q.,McLeish, M.J.,Martin, J.L.
Enzyme Adaptation to Inhibitor Binding: A Cryptic Binding Site in Phenylethanolamine N-Methyltransferase
J.Med.Chem., 50:4845-4853, 2007

PubMed Abstract: Shape complementarity is a fundamental principle of inhibitor design. Here we show that an enzyme for which the crystal structure has been determined (phenylethanolamine N-methyltransferase, PNMT) conceals a cryptic binding site. This site is revealed upon binding of inhibitors that are double the size of the physiological substrate. These large inhibitors are not predicted to bind in that they protrude through the accessible surface calculated from a PNMT/7-aminosulfonyl-1,2,3,4-tetrahydroisoquinoline (SK&F 29661) crystal structure, yet they are potent inhibitors of PNMT. We determined structures of the enzyme complexed with large inhibitors and found that the volume of the active site increases by 140 A3 upon binding. Changes in active site size and shape are brought about by unfavorable side chain conformations and rigid body helix motions. The energetic cost is modest, estimated at 2-3 kcal/mol from mutational analyses. Our findings further underline the importance of protein flexibility in structure-based inhibitor design studies.

PubMed: 17845018
DOI: 10.1021/jm0703385

実験手法

X-RAY DIFFRACTION (2.2 Å)