6FJI

Joint neutron and x-ray crystal structure of human carbonic anhydrase IX mimic (apo).

Summary for 6FJI

• Entry DOI: 10.2210/pdb6fji/pdb
• Descriptor: Carbonic anhydrase 2, ZINC ION (3 entities in total)
• Functional Keywords: joint x-ray neutron diffraction, carbonic anhydrase, lyase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 29266.30

Authors

Fisher, S.Z. (deposition date: 2018-01-22, release date: 2019-02-06, Last modification date: 2024-05-01)

Primary citation

Koruza, K.,Mahon, B.P.,Blakeley, M.P.,Ostermann, A.,Schrader, T.E.,McKenna, R.,Knecht, W.,Fisher, S.Z.
Using neutron crystallography to elucidate the basis of selective inhibition of carbonic anhydrase by saccharin and a derivative.
J. Struct. Biol., 205:147-154, 2019

PubMed Abstract: 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 IX 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 IX 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.

PubMed: 30639924
DOI: 10.1016/j.jsb.2018.12.009

Experimental method

NEUTRON DIFFRACTION (2.033 Å)
X-RAY DIFFRACTION (1.6 Å)