Research output per year
Research output per year
Katarina Koruza, Brian P. Mahon, Matthew P. Blakeley, Andreas Ostermann, Tobias E. Schrader, Robert McKenna, Wolfgang Knecht, S. Zoë Fisher
Research output: Contribution to journal › Article › peer-review
Up-regulation of carbonic anhydrase IX (CA IX) expression is an indicator of metastasis and associated with poor cancer patient prognosis. CA IX has emerged as a cancer drug target but development of isoform-specific inhibitors is challenging due to other highly conserved CA isoforms. In this study, a CA IXmimic construct was used (CA II with seven point mutations introduced, to mimic CA IX active site) while maintaining CA II solubility that make it amenable to crystallography. The structures of CA IXmimic unbound and in complex with saccharin (SAC) and a saccharin-glucose conjugate (SGC) were determined using joint X-ray and neutron protein crystallography. Previously, SAC and SGC have been shown to display CA isoform inhibitor selectivity in assays and X-ray crystal structures failed to reveal the basis of this selectivity. Joint X-ray and neutron crystallographic studies have shown active site residues, solvent, and H-bonding re-organization upon SAC and SGC binding. These observations highlighted the importance of residues 67 (Asn in CA II, Gln in CA IX) and 130 (Asp in CA II, Arg in CA IX) in selective CA inhibitor targeting.
Original language | English |
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Pages (from-to) | 147-154 |
Journal | Journal of Structural Biology |
Volume | 205 |
Issue number | 2 |
Early online date | 2019 Jan 11 |
DOIs | |
Publication status | Published - 2019 |
Research output: Thesis › Doctoral Thesis (compilation)