Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 98, Issue 17, Pages 9545-9550Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.161301298
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Funding
- NIDDK NIH HHS [DK40163, R01 DK040163] Funding Source: Medline
- NIGMS NIH HHS [GM34182, R01 GM034182, GM45614] Funding Source: Medline
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Overexpression of the zinc enzyme carbonic anhydrase (CA: EC 4.2.1.1) XII is observed in certain human cancers. This bitopic membrane protein contains an N-terminal extracellular catalytic domain, a membrane-spanning a-helix, and a small intracellular C-terminal domain. We have determined the three-dimensional structure of the extracellular catalytic domain of human CA XII by x-ray crystallographic methods at 1.55-Angstrom resolution. The structure reveals a prototypical CA fold; however, two CA XII domains associate to form an isologous dimer, an observation that is confirmed by studies of the enzyme in solution. The identification of signature GXXXG and GXXXS motifs in the transmembrane sequence that facilitate helix-helix association is additionally consistent with dimeric architecture. The dimer interface is situated so that the active site clefts of each monomer are clearly exposed on one face of the dimer, and the C-termini are located together on the opposite face of the dimer to facilitate membrane interaction. The amino acid composition of the active-site cleft closely resembles that of the other CA isozymes in the immediate vicinity of the catalytic zinc ion, but differs in the region of the nearby a-helical 130's segment. The structure of the CA Xii-acetazolamide complex is also reported at 1.50-Angstrom resolution, and prospects for the design of CA XII-specific inhibitors of possible chemotherapeutic value are discussed.
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