4RPL

Crystal structure of Micobacterium tuberculosis UDP-Galactopyranose mutase in complex with tetrafluorinated substrate analog UDP-F4-Galp

4RPL の概要

• エントリーDOI: 10.2210/pdb4rpl/pdb
• 関連するPDBエントリー: 1V0J 4RPG 4RPH 4RPJ 4RPK
• 分子名称: UDP-galactopyranose mutase, FLAVIN-ADENINE DINUCLEOTIDE, [(2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl (2R,5S,6R)-3,3,4,4-tetrafluoro-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl dihydrogen diphosphate (non-preferred name), ... (4 entities in total)
• 機能のキーワード: udp-galactopyranose mutase, mtugm, flavoenzyme, fad, isomerase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 141960.49

構造登録者

Van Straaten, K.E.,Sanders, D.A.R. (登録日: 2014-10-30, 公開日: 2015-01-21, 最終更新日: 2023-09-20)

主引用文献

van Straaten, K.E.,Kuttiyatveetil, J.R.,Sevrain, C.M.,Villaume, S.A.,Jimenez-Barbero, J.,Linclau, B.,Vincent, S.P.,Sanders, D.A.
Structural Basis of Ligand Binding to UDP-Galactopyranose Mutase from Mycobacterium tuberculosis Using Substrate and Tetrafluorinated Substrate Analogues.
J.Am.Chem.Soc., 137:1230-1244, 2015

PubMed Abstract: UDP-Galactopyranose mutase (UGM) is a flavin-containing enzyme that catalyzes the reversible conversion of UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf) and plays a key role in the biosynthesis of the mycobacterial cell wall galactofuran. A soluble, active form of UGM from Mycobacterium tuberculosis (MtUGM) was obtained from a dual His6-MBP-tagged MtUGM construct. We present the first complex structures of MtUGM with bound substrate UDP-Galp (both oxidized flavin and reduced flavin). In addition, we have determined the complex structures of MtUGM with inhibitors (UDP and the dideoxy-tetrafluorinated analogues of both UDP-Galp (UDP-F4-Galp) and UDP-Galf (UDP-F4-Galf)), which represent the first complex structures of UGM with an analogue in the furanose form, as well as the first structures of dideoxy-tetrafluorinated sugar analogues bound to a protein. These structures provide detailed insight into ligand recognition by MtUGM and show an overall binding mode similar to those reported for other prokaryotic UGMs. The binding of the ligand induces conformational changes in the enzyme, allowing ligand binding and active-site closure. In addition, the complex structure of MtUGM with UDP-F4-Galf reveals the first detailed insight into how the furanose moiety binds to UGM. In particular, this study confirmed that the furanoside adopts a high-energy conformation ((4)E) within the catalytic pocket. Moreover, these investigations provide structural insights into the enhanced binding of the dideoxy-tetrafluorinated sugars compared to unmodified analogues. These results will help in the design of carbohydrate mimetics and drug development, and show the enormous possibilities for the use of polyfluorination in the design of carbohydrate mimetics.

PubMed: 25562380
DOI: 10.1021/ja511204p

実験手法

X-RAY DIFFRACTION (2.2499 Å)