4YXI

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

Summary for 4YXI

• Entry DOI: 10.2210/pdb4yxi/pdb
• Related: 4YX4
• Descriptor: Carbonic anhydrase 2, ZINC ION, MERCURIBENZOIC ACID, ... (6 entities in total)
• Functional Keywords: protein-inhibitor complex, lyase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P00918
• Total number of polymer chains: 1
• Total formula weight: 30110.70

Authors

Rechlin, C.,Heine, A.,Klebe, G. (deposition date: 2015-03-23, release date: 2016-02-03, Last modification date: 2024-01-10)

Primary citation

Gaspari, R.,Rechlin, C.,Heine, A.,Bottegoni, G.,Rocchia, W.,Schwarz, D.,Bomke, J.,Gerber, H.D.,Klebe, G.,Cavalli, A.
Kinetic and Structural Insights into the Mechanism of Binding of Sulfonamides to Human Carbonic Anhydrase by Computational and Experimental Studies.
J.Med.Chem., 59:4245-4256, 2016

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.

PubMed: 26700575
DOI: 10.1021/acs.jmedchem.5b01643

Experimental method

X-RAY DIFFRACTION (0.96 Å)