Journal Article

FZJ-2020-00325

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Using neutron crystallography to elucidate the basis of selective inhibition of carbonic anhydrase by saccharin and a derivative

Koruza, K. ; Mahon, B. P. ; Blakeley, M. P. ; Ostermann, A. ; Schrader, T. E.FZJ* ; McKenna, R. ; Knecht, W. ; Fisher, S. Z. (Corresponding author)

2019
Elsevier San Diego, Calif.

This record in other databases:      

Please use a persistent id in citations: http://hdl.handle.net/2128/24014  doi:10.1016/j.jsb.2018.12.009

Abstract: Up-regulation of carbonic anhydrase IX (CA IX) expression is an indicator of metastasis and associated with poorcancer patient prognosis. CA IX has emerged as a cancer drug target but development of isoform-specific inhibitorsis 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 thatmake 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 crystalstructures failed to reveal the basis of this selectivity. Joint X-ray and neutron crystallographic studies haveshown active site residues, solvent, and H-bonding re-organization upon SAC and SGC binding. These observationshighlighted the importance of residues 67 (Asn in CA II, Gln in CA IX) and 130 (Asp in CA II, Arg in CAIX) in selective CA inhibitor targeting.

Keyword(s): Health and Life (1st) ; Biology (2nd)

---

Contributing Institute(s):

1. JCNS-FRM-II (JCNS-FRM-II)
2. Neutronenstreuung (JCNS-1)
3. Heinz Maier-Leibnitz Zentrum (MLZ)

Research Program(s):

1. 6G4 - Jülich Centre for Neutron Research (JCNS) (POF3-623) (POF3-623)
2. 6G15 - FRM II / MLZ (POF3-6G15) (POF3-6G15)
3. 6215 - Soft Matter, Health and Life Sciences (POF3-621) (POF3-621)

Experiment(s):

1. BIODIFF: Diffractometer for large unit cells (NL1)

Appears in the scientific report 2019

---

Database coverage:
; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

---