5AGV

The sliding clamp of Mycobacterium tuberculosis in complex with a natural product.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.93 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.171 

wwPDB Validation   3D Report Full Report


This is version 4.0 of the entry. See complete history


Literature

Antibiotics. Targeting Dnan for Tuberculosis Therapy Using Novel Griselimycins.

Kling, A.Lukat, P.Almeida, D.V.Bauer, A.Fontaine, E.Sordello, S.Zaburannyi, N.Herrmann, J.Wenzel, S.C.Konig, C.Ammerman, N.C.Barrio, M.B.Borchers, K.Bordon-Pallier, F.Bronstrup, M.Courtemanche, G.Gerlitz, M.Geslin, M.Hammann, P.Heinz, D.W.Hoffmann, H.Klieber, S.Kohlmann, M.Kurz, M.Lair, C.Matter, H.Nuermberger, E.Tyagi, S.Fraisse, L.Grosset, J.H.Lagrange, S.Muller, R.

(2015) Science 348: 1106

  • DOI: https://doi.org/10.1126/science.aaa4690
  • Primary Citation of Related Structures:  
    5AGU, 5AGV, 5AH2, 5AH4

  • PubMed Abstract: 

    The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.


  • Organizational Affiliation

    Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology, Saarland University, 66123 Saarbrücken, Germany. German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DNA POLYMERASE III SUBUNIT BETA
A, B
406Mycobacterium tuberculosis H37RvMutation(s): 0 
EC: 2.7.7.7
UniProt
Find proteins for P9WNU1 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WNU1 
Go to UniProtKB:  P9WNU1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WNU1
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLOHEXYL GRISELIMYCIN
C, D
11Streptomyces muensisMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
BU3
Query on BU3

Download Ideal Coordinates CCD File 
AA [auth B],
L [auth A],
M [auth A],
N [auth A],
Z [auth B]
(R,R)-2,3-BUTANEDIOL
C4 H10 O2
OWBTYPJTUOEWEK-QWWZWVQMSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
E [auth A]
P [auth B]
Q [auth B]
R [auth B]
S [auth B]
E [auth A],
P [auth B],
Q [auth B],
R [auth B],
S [auth B],
T [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
F [auth A]
G [auth A]
H [auth A]
I [auth A]
J [auth A]
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
O [auth B],
U [auth B],
V [auth B],
W [auth B],
X [auth B],
Y [auth B]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Modified Residues  4 Unique
IDChains TypeFormula2D DiagramParent
MP8
Query on MP8
C, D
L-PEPTIDE LINKINGC6 H11 N O2PRO
MVA
Query on MVA
C, D
L-PEPTIDE LINKINGC6 H13 N O2VAL
NZC
Query on NZC
C, D
L-PEPTIDE LINKINGC5 H11 N O3THR
PH6
Query on PH6
C, D
L-PEPTIDE LINKINGC11 H19 N O2PRO
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.93 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.171 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.869α = 90
b = 89.764β = 95.14
c = 81.928γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-06-03
    Type: Initial release
  • Version 1.1: 2015-06-17
    Changes: Database references
  • Version 1.2: 2015-06-24
    Changes: Derived calculations
  • Version 2.0: 2017-06-14
    Changes: Advisory, Atomic model, Derived calculations
  • Version 3.0: 2019-04-24
    Changes: Data collection, Polymer sequence
  • Version 4.0: 2024-01-10
    Changes: Atomic model, Data collection, Database references, Derived calculations, Other, Refinement description, Structure summary