4YWP
Sucrose Binding Site in genetically engineered Carbonic anhydrase IX
Summary for 4YWP
| Entry DOI | 10.2210/pdb4ywp/pdb |
| Related | 4ZAO |
| Related PRD ID | PRD_900003 |
| Descriptor | Carbonic anhydrase 2, beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose, ZINC ION, ... (4 entities in total) |
| Functional Keywords | alpha-carbonic anhydrase, ca ix mimic, sucrose, lyase |
| Biological source | Homo sapiens (Human) |
| Cellular location | Cytoplasm : P00918 |
| Total number of polymer chains | 1 |
| Total formula weight | 29252.17 |
| Authors | Pinard, M.A.,Aggarwal, M. (deposition date: 2015-03-20, release date: 2015-10-14, Last modification date: 2023-09-27) |
| Primary citation | Pinard, M.A.,Aggarwal, M.,Mahon, B.P.,Tu, C.,McKenna, R. A sucrose-binding site provides a lead towards an isoform-specific inhibitor of the cancer-associated enzyme carbonic anhydrase IX. Acta Crystallogr F Struct Biol Commun, 71:1352-1358, 2015 Cited by PubMed Abstract: Human carbonic anhydrase (CA; EC 4.2.1.1) isoform IX (CA IX) is an extracellular zinc metalloenzyme that catalyzes the reversible hydration of CO2 to HCO3(-), thereby playing a role in pH regulation. The majority of normal functioning cells exhibit low-level expression of CA IX. However, in cancer cells CA IX is upregulated as a consequence of a metabolic transition known as the Warburg effect. The upregulation of CA IX for cancer progression has drawn interest in it being a potential therapeutic target. CA IX is a transmembrane protein, and its purification, yield and crystallization have proven challenging to structure-based drug design, whereas the closely related cytosolic soluble isoform CA II can be expressed and crystallized with ease. Therefore, we have utilized structural alignments and site-directed mutagenesis to engineer a CA II that mimics the active site of CA IX. In this paper, the X-ray crystal structure of this CA IX mimic in complex with sucrose is presented and has been refined to a resolution of 1.5 Å, an Rcryst of 18.0% and an Rfree of 21.2%. The binding of sucrose at the entrance to the active site of the CA IX mimic, and not CA II, in a non-inhibitory mechanism provides a novel carbohydrate moiety binding site that could be further exploited to design isoform-specific inhibitors of CA IX. PubMed: 26457530DOI: 10.1107/S2053230X1501239X PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.45 Å) |
Structure validation
Download full validation report
