Crystal structure of the secretory form of membrane-associated human carbonic anhydrase IV at 2.8-Å resolution

Travis Stams, Satish K. Nair, Torayuki Okuyama, Abdul Waheed, William S. Sly, David W. Christianson

Research output: Contribution to journalArticlepeer-review


It has recently been demonstrated that the C-terminal deletion mutant of recombinant human carbonic anhydrase IV (G267X CA IV) converts the normally glycosylphosphatidylinositol-anchored enzyme into a soluble secretory form which has the same catalytic properties as the membrane-associated enzyme purified from human tissues. Wc have determined the three-dimensional structure of the secretory form of human CA IV by x-ray cristallographic methods to a resolution of 2.8 Å. Although the zinc binding site and the hydrophobic substrate binding pocket of CA IV are generally similar to those of other mammalian isozymes, unique structural differences are found elsewhere in the active sin. Two disufide linkages, Cys-6-Cys-11G and Cys-23-Cys-203, stabilize the conformation of the N-terminal domain. The latter disulfide additionally stabilizes an active site loop containing a cis-peptide linkage between Pro-201 and Thr-202 (this loop contains catalytic residue Thr-199). On the opposite side of the active site, the Val-131-Asp-136 segment adopts an extended loop conformation instead of an α-helix conformation as found in other isozymes. Finally, the C terminus is surrounded by a substantial electropositive surface potential, which is likely to stabilize the interaction of CA IV with the negatively charged phospholipid headgroups of the membrane. These structural features are unique to CA IV and provide a framework for the design of sulfonamide inhibitors selective for this particular isozyme.

Original languageEnglish (US)
Pages (from-to)13589-13594
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number24
StatePublished - Nov 26 1996
Externally publishedYes


  • Carbon dioxide hydration
  • Protein crystallography
  • Zinc enzyme

ASJC Scopus subject areas

  • General


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