Structure of testis ACE glycosylation mutants and evidence for conserved domain movement

Biochemistry. 2006 Oct 24;45(42):12654-63. doi: 10.1021/bi061146z.

Abstract

Human angiotensin-converting enzyme is an important drug target for which little structural information has been available until recent years. The slow progress in obtaining a crystal structure was due to the problem of surface glycosylation, a difficulty that has thus far been overcome by the use of a glucosidase-1 inhibitor in the tissue culture medium. However, the prohibitive cost of these inhibitors and incomplete glucosidase inhibition makes alternative routes to minimizing the N-glycan heterogeneity desirable. Here, glycosylation in the testis isoform (tACE) has been reduced by Asn-Gln point mutations at N-glycosylation sites, and the crystal structures of mutants having two and four intact sites have been solved to 2.0 A and 2.8 A, respectively. Both mutants show close structural identity with the wild-type. A hinge mechanism is proposed for substrate entry into the active cleft, based on homology to human ACE2 at the levels of sequence and flexibility. This is supported by normal-mode analysis that reveals intrinsic flexibility about the active site of tACE. Subdomain II, containing bound chloride and zinc ions, is found to have greater stability than subdomain I in the structures of three ACE homologues. Crystallizable glycosylation mutants open up new possibilities for cocrystallization studies to aid the design of novel ACE inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • CHO Cells
  • Conserved Sequence
  • Cricetinae
  • Glycosylation
  • Humans
  • Isoenzymes / chemistry
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Peptidyl-Dipeptidase A / chemistry
  • Peptidyl-Dipeptidase A / genetics*
  • Peptidyl-Dipeptidase A / metabolism
  • Protein Conformation
  • Protein Structure, Secondary
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Testis
  • Transfection

Substances

  • Isoenzymes
  • Peptidyl-Dipeptidase A

Associated data

  • PDB/2IUL
  • PDB/2IUX
  • PDB/R2IULSF
  • PDB/R2IUXSF