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Crystal structure of the catalytic-domain of human carbonic anhydrase IX at 1.6 angstrom resolution
Structural highlights
FunctionCAH9_HUMAN Reversible hydration of carbon dioxide. Participates in pH regulation. May be involved in the control of cell proliferation and transformation. Appears to be a novel specific biomarker for a cervical neoplasia.[1] Publication Abstract from PubMedHuman carbonic anhydrase IX (hCA IX) expression in many cancers is associated with hypoxic tumors and poor patient outcome. Inhibitors of hCA IX have been used as anti-cancer agents with some entering Phase I clinical trials. hCA IX is a transmembrane protein whose catalytic domain faces the extracellular tumor milieu, which is typically associated with an acidic microenvironment. Here, we show that the catalytic domain of hCA IX (hCA IX-c) exhibits the necessary biochemical/biophysical properties that allow for low pH stability and activity. Furthermore, the unfolding process of hCA IX-c appears to be reversible and its catalytic efficiency is suggested to be correlated directly with its stability between 3.0<pH<8.0 but not at pH>8.0. To rationalize this, we determined the X-ray crystal structure of hCA IX-c to 1.6 A resolution. Insights from this study suggest an understanding of hCA IX-c stability and activity in low pH tumor microenvironments, and may be applicable to determining pH-related effects on other enzymes. Structure of carbonic anhydrase IX is adapted for low pH catalysis.,Mahon BP, Bhatt A, Socorro L, Driscoll JM, Okoh C, Lomelino CL, Mboge MY, Kurian JJ, Tu C, Agbandje-McKenna M, Frost SC, McKenna R Biochemistry. 2016 Jul 20. PMID:27439028[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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