4MLT

Structure of a monodentate 3-hydroxy-4H-pyran-4-thione ligand bound to hCAII


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.176 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

'Unconventional' coordination chemistry by metal chelating fragments in a metalloprotein active site.

Martin, D.P.Blachly, P.G.Marts, A.R.Woodruff, T.M.de Oliveira, C.A.McCammon, J.A.Tierney, D.L.Cohen, S.M.

(2014) J Am Chem Soc 136: 5400-5406

  • DOI: https://doi.org/10.1021/ja500616m
  • Primary Citation of Related Structures:  
    4MLT, 4MLX

  • PubMed Abstract: 

    The binding of three closely related chelators: 5-hydroxy-2-methyl-4H-pyran-4-thione (allothiomaltol, ATM), 3-hydroxy-2-methyl-4H-pyran-4-thione (thiomaltol, TM), and 3-hydroxy-4H-pyran-4-thione (thiopyromeconic acid, TPMA) to the active site of human carbonic anhydrase II (hCAII) has been investigated. Two of these ligands display a monodentate mode of coordination to the active site Zn(2+) ion in hCAII that is not recapitulated in model complexes of the enzyme active site. This unprecedented binding mode in the hCAII-thiomaltol complex has been characterized by both X-ray crystallography and X-ray spectroscopy. In addition, the steric restrictions of the active site force the ligands into a 'flattened' mode of coordination compared with inorganic model complexes. This change in geometry has been shown by density functional computations to significantly decrease the strength of the metal-ligand binding. Collectively, these data demonstrate that the mode of binding by small metal-binding groups can be significantly influenced by the protein active site. Diminishing the strength of the metal-ligand bond results in unconventional modes of metal coordination not found in typical coordination compounds or even carefully engineered active site models, and understanding these effects is critical to the rational design of inhibitors that target clinically relevant metalloproteins.


  • Organizational Affiliation

    Department of Chemistry and Biochemistry, §Pharmacology, and ∥Howard Hughes Medical Institute, University of California, San Diego , La Jolla, California 92093, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 2260Homo sapiensMutation(s): 0 
Gene Names: CA2
EC: 4.2.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00918 (Homo sapiens)
Explore P00918 
Go to UniProtKB:  P00918
PHAROS:  P00918
GTEx:  ENSG00000104267 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00918
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
TM4 Binding MOAD:  4MLT Ki: 1.40e+6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.176 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.145α = 90
b = 41.472β = 104.19
c = 72.029γ = 90
Software Package:
Software NamePurpose
APEXdata collection
PHASERphasing
REFMACrefinement
APEXdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-02
    Type: Initial release
  • Version 1.1: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description