6B5E

Mycobacterium tuberculosis RmlA in complex with dTDP-glucose


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.174 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

The structure of glucose-1-phosphate thymidylyltransferase from Mycobacterium tuberculosis reveals the location of an essential magnesium ion in the RmlA-type enzymes.

Brown, H.A.Thoden, J.B.Tipton, P.A.Holden, H.M.

(2018) Protein Sci 27: 441-450

  • DOI: https://doi.org/10.1002/pro.3333
  • Primary Citation of Related Structures:  
    6B5E, 6B5K

  • PubMed Abstract: 

    Tuberculosis, caused by the bacterium Mycobacterium tuberculosis, continues to be a major threat to populations worldwide. Whereas the disease is treatable, the drug regimen is arduous at best with the use of four antimicrobials over a six-month period. There is clearly a pressing need for the development of new therapeutics. One potential target for structure-based drug design is the enzyme RmlA, a glucose-1-phosphate thymidylyltransferase. This enzyme catalyzes the first step in the biosynthesis of l-rhamnose, which is a deoxysugar critical for the integrity of the bacterium's cell wall. Here, we report the X-ray structures of M. tuberculosis RmlA in complex with either dTTP or dTDP-glucose to 1.6 Å and 1.85 Å resolution, respectively. In the RmlA/dTTP complex, two magnesium ions were observed binding to the nucleotide, both ligated in octahedral coordination spheres. In the RmlA/dTDP-glucose complex, only a single magnesium ion was observed. Importantly, for RmlA-type enzymes with known three-dimensional structures, not one model shows the position of the magnesium ion bound to the nucleotide-linked sugar. As such, this investigation represents the first direct observation of the manner in which a magnesium ion is coordinated to the RmlA product and thus has important ramifications for structure-based drug design. In the past, molecular modeling procedures have been employed to derive a three-dimensional model of the M. tuberculosis RmlA for drug design. The X-ray structures presented herein provide a superior molecular scaffold for such endeavors in the treatment of one of the world's deadliest diseases.


  • Organizational Affiliation

    Department of Biochemistry, University of Wisconsin, Madison, WI, 53706, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glucose-1-phosphate thymidylyltransferase
A, B, C, D, E
A, B, C, D, E, F, G, H
296Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: rmlArfbARv0334
EC: 2.7.7.24
UniProt
Find proteins for P9WH13 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WH13 
Go to UniProtKB:  P9WH13
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WH13
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
DAU
Query on DAU

Download Ideal Coordinates CCD File 
AA [auth E]
CA [auth F]
DA [auth F]
FA [auth G]
I [auth A]
AA [auth E],
CA [auth F],
DA [auth F],
FA [auth G],
I [auth A],
IA [auth H],
N [auth B],
S [auth C],
W [auth D],
Z [auth E]
2'DEOXY-THYMIDINE-5'-DIPHOSPHO-ALPHA-D-GLUCOSE
C16 H26 N2 O16 P2
YSYKRGRSMLTJNL-URARBOGNSA-N
TYD
Query on TYD

Download Ideal Coordinates CCD File 
HA [auth G]
K [auth A]
KA [auth H]
Q [auth B]
U [auth C]
HA [auth G],
K [auth A],
KA [auth H],
Q [auth B],
U [auth C],
Y [auth D]
THYMIDINE-5'-DIPHOSPHATE
C10 H16 N2 O11 P2
UJLXYODCHAELLY-XLPZGREQSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
M [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CL
Query on CL

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L [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
MG
Query on MG

Download Ideal Coordinates CCD File 
BA [auth E]
EA [auth F]
GA [auth G]
J [auth A]
JA [auth H]
BA [auth E],
EA [auth F],
GA [auth G],
J [auth A],
JA [auth H],
O [auth B],
P [auth B],
T [auth C],
X [auth D]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
R [auth B],
V [auth C]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.174 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.323α = 90
b = 111.264β = 90
c = 290.363γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM115921

Revision History  (Full details and data files)

  • Version 1.0: 2018-02-21
    Type: Initial release
  • Version 1.1: 2020-01-01
    Changes: Author supporting evidence
  • Version 1.2: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description