Crystal structures of zinc-free and -bound heme domain of human inducible nitric-oxide synthase. Implications for dimer stability and comparison with endothelial nitric-oxide synthase

Academic Article

Abstract

  • The crystal structures of the heme domain of human inducible nitric- oxide synthase (NOS-2) in zinc-free and -bound states have been solved. In the zinc-free structure, two symmetry-related cysteine residues form a disulfide bond. In the zinc-bound state, these same two cysteine residues form part of a zinc-tetrathiolate (ZnS4) center indistinguishable from that observed in the endothelial isoform (NOS-3). As in NOS-3, ZnS4 plays a key role in stabilizing intersubunit contacts and in maintaining the integrity of the cofactor (tetrahydrobiopterin) binding site of NOS-2. A comparison of NOS-2 and NOS-3 structures illustrates the conservation of quaternary structure, tertiary topology, and substrate and cofactor binding sites, in addition to providing insights on isoform-specific inhibitor design. The structural comparison also reveals that pterin binding does not preferentially stabilize the dimer interface of NOS-2 over NOS-3.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Author List

  • Li H; Raman CS; Glaser CB; Blasko E; Young TA; Parkinson JF; Whitlow M; Poulos TL
  • Start Page

  • 21276
  • End Page

  • 21284
  • Volume

  • 274
  • Issue

  • 30