5BR7: Structure Of Udp-galactopyranose Mutase From Corynebacterium Diphtheriae In Complex With Citrate Ion

Citation:
Abstract
UDP-galactopyranose mutase (Glf or UGM) catalyzes the formation of uridine 5'-diphosphate-alpha-d-galactofuranose (UDP-Galf) from UDP-galactopyranose (UDP-Galp). The enzyme is required for the production of Galf-containing glycans. UGM is absent in mammals, but members of the Corynebacterineae suborder require UGM for cell envelope biosynthesis. The need for UGM in some pathogens has prompted the search for inhibitors that could serve as antibiotic leads. Optimizing inhibitor potency, however, has been challenging. The UGM from Klebsiella pneumoniae (KpUGM), which is not required for viability, is more effectively impeded by small-molecule inhibitors than are essential UGMs from species such as Mycobacterium tuberculosis or Corynebacterium diphtheriae. Why KpUGM is more susceptible to inhibition than other orthologs is not clear. One potential source of difference is UGM ortholog conformation. We previously determined a structure of CdUGM bound to a triazolothiadiazine inhibitor in the open form, but it was unclear whether the small-molecule inhibitor bound this form or to the closed form. By varying the terminal tag (CdUGM-His6 and GSG-CdUGM), we crystallized CdUGM to capture the enzyme in different conformations. These structures reveal a pocket in the active site that can be exploited to augment inhibitor affinity. Moreover, they suggest the inhibitor binds the open form of most prokaryotic UGMs but can bind the closed form of KpUGM. This model and the structures suggest strategies for optimizing inhibitor potency by exploiting UGM conformational flexibility.
PDB ID: 5BR7Download
MMDB ID: 139693
PDB Deposition Date: 2015/5/29
Updated in MMDB: 2017/08
Experimental Method:
x-ray diffraction
Resolution: 1.95  Å
Source Organism:
Similar Structures:
Biological Unit for 5BR7: dimeric; determined by author
Molecular Components in 5BR7
Label Count Molecule
Proteins (2 molecules)
2
Udp-galactopyranose Mutase
Molecule annotation
Chemicals (22 molecules)
1
2
2
8
3
4
4
6
5
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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