4CVG

Structure of bovine endothelial nitric oxide synthase heme domain (H4B-free) supplemented with 50uM Zn acetate and with poor binding of 6-acetyl-2-amino-7,7-dimethyl-7,8-dihydropteridin-4(3H)-one.

Summary for 4CVG

• Entry DOI: 10.2210/pdb4cvg/pdb
• Related: 4CUL 4CUM 4CUN
• Descriptor: NITRIC OXIDE SYNTHASE, ENDOTHELIAL, ARGININE, PROTOPORPHYRIN IX CONTAINING FE, ... (7 entities in total)
• Functional Keywords: oxidoreductase, cofactor analog complex
• Biological source: BOS TAURUS (CATTLE)
• Cellular location: Cell membrane: P29473
• Total number of polymer chains: 2
• Total formula weight: 101313.01

Authors

Chreifi, G.,Li, H.,Poulos, T.L. (deposition date: 2014-03-25, release date: 2014-05-28, Last modification date: 2024-10-23)

Primary citation

Chreifi, G.,Li, H.,Mcinnes, C.R.,Gibson, C.L.,Suckling, C.J.,Poulos, T.L.
Communication between the Zinc and Tetrahydrobiopterin Binding Sites in Nitric Oxide Synthase.
Biochemistry, 53:4216-, 2014

PubMed Abstract: The nitric oxide synthase (NOS) dimer is stabilized by a Zn(2+) ion coordinated to four symmetry-related Cys residues exactly along the dimer 2-fold axis. Each of the two essential tetrahydrobiopterin (H4B) molecules in the dimer interacts directly with the heme, and each H4B molecule is ~15 Å from the Zn(2+). We have determined the crystal structures of the bovine endothelial NOS dimer oxygenase domain bound to three different pterin analogues, which reveal an intimate structural communication between the H4B and Zn(2+) sites. The binding of one of these compounds, 6-acetyl-2-amino-7,7-dimethyl-7,8-dihydro-4(3H)-pteridinone (1), to the pterin site and Zn(2+) binding are mutually exclusive. Compound 1 both directly and indirectly disrupts hydrogen bonding between key residues in the Zn(2+) binding motif, resulting in destabilization of the dimer and a complete disruption of the Zn(2+) site. Addition of excess Zn(2+) stabilizes the Zn(2+) site at the expense of weakened binding of 1. The unique structural features of 1 that disrupt the dimer interface are extra methyl groups that extend into the dimer interface and force a slight opening of the dimer, thus resulting in disruption of the Zn(2+) site. These results illustrate a very delicate balance of forces and structure at the dimer interface that must be maintained to properly form the Zn(2+), pterin, and substrate binding sites.

PubMed: 24819538
DOI: 10.1021/BI5003986

Experimental method

X-RAY DIFFRACTION (2.31 Å)