5VWT

Crystal structure of oxidized Aspergillus fumigatus UDP-galactopyranose mutase complexed with NADPH

「4GDC」から置き換えられました

5VWT の概要

• エントリーDOI: 10.2210/pdb5vwt/pdb
• 分子名称: UDP-galactopyranose mutase, FLAVIN-ADENINE DINUCLEOTIDE, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: flavin adenine dinucleotide binding, nucleotide binding, mutase, isomerase
• 由来する生物種: Neosartorya fumigata (Aspergillus fumigatus)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 235982.70

構造登録者

Tanner, J.J. (登録日: 2017-05-22, 公開日: 2017-05-31, 最終更新日: 2023-10-04)

主引用文献

Dhatwalia, R.,Singh, H.,Solano, L.M.,Oppenheimer, M.,Robinson, R.M.,Ellerbrock, J.F.,Sobrado, P.,Tanner, J.J.
Identification of the NAD(P)H binding site of eukaryotic UDP-galactopyranose mutase.
J. Am. Chem. Soc., 134:18132-18138, 2012

PubMed Abstract: UDP-galactopyranose mutase (UGM) plays an essential role in galactofuranose biosynthesis in microorganisms by catalyzing the conversion of UDP-galactopyranose to UDP-galactofuranose. The enzyme has gained attention recently as a promising target for the design of new antifungal, antitrypanosomal, and antileishmanial agents. Here we report the first crystal structure of UGM complexed with its redox partner NAD(P)H. Kinetic protein crystallography was used to obtain structures of oxidized Aspergillus fumigatus UGM (AfUGM) complexed with NADPH and NADH, as well as reduced AfUGM after dissociation of NADP(+). NAD(P)H binds with the nicotinamide near the FAD isoalloxazine and the ADP moiety extending toward the mobile 200s active site flap. The nicotinamide riboside binding site overlaps that of the substrate galactopyranose moiety, and thus NADPH and substrate binding are mutually exclusive. On the other hand, the pockets for the adenine of NADPH and uracil of the substrate are distinct and separated by only 6 Å, which raises the possibility of designing novel inhibitors that bind both sites. All 12 residues that contact NADP(H) are conserved among eukaryotic UGMs. Residues that form the AMP pocket are absent in bacterial UGMs, which suggests that eukaryotic and bacterial UGMs have different NADP(H) binding sites. The structures address the longstanding question of how UGM binds NAD(P)H and provide new opportunities for drug discovery.

PubMed: 23036087
DOI: 10.1021/ja308188z

実験手法

X-RAY DIFFRACTION (2.75 Å)