4RPJ

Crystal structure of Micobacterium tuberculosis UDP-Galactopyranose mutase in complex with UDP

Summary for 4RPJ

• Entry DOI: 10.2210/pdb4rpj/pdb
• Related: 1V0J 4RPG 4RPH 4RPK 4RPL
• Descriptor: UDP-galactopyranose mutase, FLAVIN-ADENINE DINUCLEOTIDE, URIDINE-5'-DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: udp-galactopyranose mutase, mtugm, flavoenzyme, fad, isomerase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 3
• Total formula weight: 141354.18

Authors

Van Straaten, K.E.,Sanders, D.A.R. (deposition date: 2014-10-30, release date: 2015-01-21, Last modification date: 2023-09-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.5 Å)