3S75

The origin of the hydrophobic effect in the molecular recognition of arylsulfonamides by carbonic anhydrase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.151 
  • R-Value Observed: 0.153 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Mechanism of the hydrophobic effect in the biomolecular recognition of arylsulfonamides by carbonic anhydrase.

Snyder, P.W.Mecinovic, J.Moustakas, D.T.Thomas, S.W.Harder, M.Mack, E.T.Lockett, M.R.Heroux, A.Sherman, W.Whitesides, G.M.

(2011) Proc Natl Acad Sci U S A 108: 17889-17894

  • DOI: https://doi.org/10.1073/pnas.1114107108
  • Primary Citation of Related Structures:  
    3S71, 3S72, 3S73, 3S74, 3S75, 3S76, 3S77, 3S78

  • PubMed Abstract: 

    The hydrophobic effect--a rationalization of the insolubility of nonpolar molecules in water--is centrally important to biomolecular recognition. Despite extensive research devoted to the hydrophobic effect, its molecular mechanisms remain controversial, and there are still no reliably predictive models for its role in protein-ligand binding. Here we describe a particularly well-defined system of protein and ligands--carbonic anhydrase and a series of structurally homologous heterocyclic aromatic sulfonamides--that we use to characterize hydrophobic interactions thermodynamically and structurally. In binding to this structurally rigid protein, a set of ligands (also defined to be structurally rigid) shows the expected gain in binding free energy as hydrophobic surface area is added. Isothermal titration calorimetry demonstrates that enthalpy determines these increases in binding affinity, and that changes in the heat capacity of binding are negative. X-ray crystallography and molecular dynamics simulations are compatible with the proposal that the differences in binding between the homologous ligands stem from changes in the number and organization of water molecules localized in the active site in the bound complexes, rather than (or perhaps in addition to) release of structured water from the apposed hydrophobic surfaces. These results support the hypothesis that structured water molecules--including both the molecules of water displaced by the ligands and those reorganized upon ligand binding--determine the thermodynamics of binding of these ligands at the active site of the protein. Hydrophobic effects in various contexts have different structural and thermodynamic origins, although all may be manifestations of the differences in characteristics of bulk water and water close to hydrophobic surfaces.


  • Organizational Affiliation

    Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 2A [auth B]258Homo 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
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
EVG PDBBind:  3S75 Kd: 150 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.151 
  • R-Value Observed: 0.153 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.378α = 90
b = 41.431β = 104.66
c = 72.496γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-10-19
    Type: Initial release
  • Version 1.1: 2011-12-21
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations