4YXI

Human Carbonic Anhydrase II complexed with an inhibitor with a benzenesulfonamide group (2).


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 0.96 Å
  • R-Value Free: 0.153 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.141 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Kinetic and Structural Insights into the Mechanism of Binding of Sulfonamides to Human Carbonic Anhydrase by Computational and Experimental Studies.

Gaspari, R.Rechlin, C.Heine, A.Bottegoni, G.Rocchia, W.Schwarz, D.Bomke, J.Gerber, H.D.Klebe, G.Cavalli, A.

(2016) J Med Chem 59: 4245-4256

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01643
  • Primary Citation of Related Structures:  
    4YX4, 4YXI, 4YXO, 4YXU, 4YYT

  • PubMed Abstract: 

    The binding of sulfonamides to human carbonic anhydrase II (hCAII) is a complex and long-debated example of protein-ligand recognition and interaction. In this study, we investigate the para-substituted n-alkyl and hydroxyethylene-benzenesulfonamides, providing a complete reconstruction of their binding pathway to hCAII by means of large-scale molecular dynamics simulations, density functional calculations, surface plasmon resonance (SPR) measurements, and X-ray crystallography experiments. Our analysis shows that the protein-ligand association rate (kon) dramatically increases with the ligand's hydrophobicity, pointing to the existence of a prebinding stage largely stabilized by a favorable packing of the ligand's apolar moieties with the hCAII "hydrophobic wall". The characterization of the binding pathway allows an unprecedented understanding of the structure-kinetic relationship in hCAII/benzenesulfonamide complexes, depicting a paradigmatic scenario for the multistep binding process in protein-ligand systems.


  • Organizational Affiliation

    Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , 16163 Genova, Italy.


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
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
4J8 BindingDB:  4YXI Ki: min: 320, max: 3.20e+5 (nM) from 3 assay(s)
Kd: min: 0.06, max: 4.3 (nM) from 3 assay(s)
IC50: min: 580, max: 715 (nM) from 2 assay(s)
Binding MOAD:  4YXI Kd: 318.8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 0.96 Å
  • R-Value Free: 0.153 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.141 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.463α = 90
b = 41.529β = 104.48
c = 72.453γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European Union/ERC268145-DrugProfilBind

Revision History  (Full details and data files)

  • Version 1.0: 2016-02-03
    Type: Initial release
  • Version 1.1: 2016-05-25
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Refinement description