6ZYR

Structure of IMP-1 with 2-Mercaptomethyl-thiazolidine L-anti-1b


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.87 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

2-Mercaptomethyl-thiazolidines use conserved aromatic-S interactions to achieve broad-range inhibition of metallo-beta-lactamases.

Rossi, M.A.Martinez, V.Hinchliffe, P.Mojica, M.F.Castillo, V.Moreno, D.M.Smith, R.Spellberg, B.Drusano, G.L.Banchio, C.Bonomo, R.A.Spencer, J.Vila, A.J.Mahler, G.

(2021) Chem Sci 12: 2898-2908

  • DOI: https://doi.org/10.1039/d0sc05172a
  • Primary Citation of Related Structures:  
    6ZYN, 6ZYO, 6ZYP, 6ZYQ, 6ZYR, 6ZYS

  • PubMed Abstract: 

    Infections caused by multidrug resistant (MDR) bacteria are a major public health threat. Carbapenems are among the most potent antimicrobial agents that are commercially available to treat MDR bacteria. Bacterial production of carbapenem-hydrolysing metallo-β-lactamases (MBLs) challenges their safety and efficacy, with subclass B1 MBLs hydrolysing almost all β-lactam antibiotics. MBL inhibitors would fulfil an urgent clinical need by prolonging the lifetime of these life-saving drugs. Here we report the synthesis and activity of a series of 2-mercaptomethyl-thiazolidines (MMTZs), designed to replicate MBL interactions with reaction intermediates or hydrolysis products. MMTZs are potent competitive inhibitors of B1 MBLs in vitro ( e.g. , K i = 0.44 μM vs. NDM-1). Crystal structures of MMTZ complexes reveal similar binding patterns to the most clinically important B1 MBLs (NDM-1, VIM-2 and IMP-1), contrasting with previously studied thiol-based MBL inhibitors, such as bisthiazolidines (BTZs) or captopril stereoisomers, which exhibit lower, more variable potencies and multiple binding modes. MMTZ binding involves thiol coordination to the Zn(ii) site and extensive hydrophobic interactions, burying the inhibitor more deeply within the active site than d/l-captopril. Unexpectedly, MMTZ binding features a thioether-π interaction with a conserved active-site aromatic residue, consistent with their equipotent inhibition and similar binding to multiple MBLs. MMTZs penetrate multiple Enterobacterales, inhibit NDM-1 in situ , and restore carbapenem potency against clinical isolates expressing B1 MBLs. Based on their inhibitory profile and lack of eukaryotic cell toxicity, MMTZs represent a promising scaffold for MBL inhibitor development. These results also suggest sulphur-π interactions can be exploited for general ligand design in medicinal chemistry.


  • Organizational Affiliation

    Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR) Ocampo and Esmeralda S2002LRK Rosario Argentina [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-lactamase IMP-1
A, B, C, D
230Serratia marcescensMutation(s): 0 
EC: 3.5.2.6
UniProt
Find proteins for P52699 (Serratia marcescens)
Explore P52699 
Go to UniProtKB:  P52699
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP52699
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
QT2 (Subject of Investigation/LOI)
Query on QT2

Download Ideal Coordinates CCD File 
G [auth A],
K [auth B],
S [auth C],
W [auth D]
(2~{S},4~{R})-2-ethoxycarbonyl-5,5-dimethyl-2-(sulfanylmethyl)-1,3-thiazolidine-4-carboxylic acid
C10 H17 N O4 S2
PUOMKKVEJFJZFE-LHLIQPBNSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
I [auth B]
J [auth B]
Q [auth C]
E [auth A],
F [auth A],
I [auth B],
J [auth B],
Q [auth C],
R [auth C],
U [auth D],
V [auth D]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
H [auth A],
L [auth B],
M [auth B],
N [auth B],
O [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
ACT
Query on ACT

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T [auth C]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
NA
Query on NA

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

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.87 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.555α = 90
b = 78.003β = 90
c = 261.107γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
DIALSdata reduction
Aimlessdata 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 Allergy and Infectious Diseases (NIH/NIAID)United StatesR01AI100560

Revision History  (Full details and data files)

  • Version 1.0: 2021-01-20
    Type: Initial release
  • Version 1.1: 2021-07-07
    Changes: Database references
  • Version 1.2: 2024-01-31
    Changes: Data collection, Database references, Refinement description