5U0Y

E. coli dihydropteroate synthase complexed with an 8-mercaptoguanine derivative: [(2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)sulfanyl]acetic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.208 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

8-Mercaptoguanine Derivatives as Inhibitors of Dihydropteroate Synthase.

Dennis, M.L.Lee, M.D.Harjani, J.R.Ahmed, M.DeBono, A.J.Pitcher, N.P.Wang, Z.C.Chhabra, S.Barlow, N.Rahmani, R.Cleary, B.Dolezal, O.Hattarki, M.Aurelio, L.Shonberg, J.Graham, B.Peat, T.S.Baell, J.B.Swarbrick, J.D.

(2018) Chemistry 24: 1922-1930

  • DOI: https://doi.org/10.1002/chem.201704730
  • Primary Citation of Related Structures:  
    5U0V, 5U0W, 5U0Y, 5U0Z, 5U10, 5U11, 5U12, 5U13, 5U14, 5V79, 5V7A

  • PubMed Abstract: 

    Dihydropteroate synthase (DHPS) is an enzyme of the folate biosynthesis pathway, which catalyzes the formation of 7,8-dihydropteroate (DHPt) from 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (DHPPP) and para-aminobenzoic acid (pABA). DHPS is the long-standing target of the sulfonamide class of antibiotics that compete with pABA. In the wake of sulfa drug resistance, targeting the structurally rigid (and more conserved) pterin site has been proposed as an alternate strategy to inhibit DHPS in wild-type and sulfa drug resistant strains. Following the work on developing pterin-site inhibitors of the adjacent enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), we now present derivatives of 8-mercaptoguanine, a fragment that binds weakly within both enzymes, and quantify sub-μm binding using surface plasmon resonance (SPR) to Escherichia coli DHPS (EcDHPS). Eleven ligand-bound EcDHPS crystal structures delineate the structure-activity relationship observed providing a structural framework for the rational development of novel, substrate-envelope-compliant DHPS inhibitors.


  • Organizational Affiliation

    Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, 3052, Victoria, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydropteroate synthase
A, B
284Escherichia coli CFT073Mutation(s): 0 
Gene Names: folPc3933
EC: 2.5.1.15
UniProt
Find proteins for P0AC13 (Escherichia coli (strain K12))
Explore P0AC13 
Go to UniProtKB:  P0AC13
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0AC13
Sequence Annotations
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  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.208 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 94.936α = 90
b = 85.236β = 111.48
c = 84.775γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-12-06
    Type: Initial release
  • Version 1.1: 2018-02-14
    Changes: Database references
  • Version 1.2: 2023-10-04
    Changes: Data collection, Database references, Refinement description