1DMK

BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 4-AMINO-6-PHENYL-TETRAHYDROPTERIDINE

Summary for 1DMK

• Entry DOI: 10.2210/pdb1dmk/pdb
• Related: 1NSE
• Descriptor: NITRIC OXIDE SYNTHASE, ACETATE ION, CACODYLATE ION, ... (8 entities in total)
• Functional Keywords: alpha-beta fold, oxidoreductase
• Biological source: Bos taurus (cattle)
• Cellular location: Cell membrane: P29473
• Total number of polymer chains: 2
• Total formula weight: 102098.79

Authors

Kotsonis, P.,Frohlich, L.G.,Raman, C.S.,Li, H.,Berg, M.,Gerwig, R.,Groehn, V.,Kang, Y.,Al-Masoudi, N.,Taghavi-Moghadam, S.,Mohr, D.,Munch, U.,Schnabel, J.,Martasek, P.,Masters, B.S.,Strobel, H.,Poulos, T.,Matter, H.,Pfleiderer, W.,Schmidt, H.H. (deposition date: 1999-12-14, release date: 2000-12-20, Last modification date: 2024-02-07)

Primary citation

Kotsonis, P.,Frohlich, L.G.,Raman, C.S.,Li, H.,Berg, M.,Gerwig, R.,Groehn, V.,Kang, Y.,Al-Masoudi, N.,Taghavi-Moghadam, S.,Mohr, D.,Munch, U.,Schnabel, J.,Martasek, P.,Masters, B.S.,Strobel, H.,Poulos, T.,Matter, H.,Pfleiderer, W.,Schmidt, H.H.
Structural basis for pterin antagonism in nitric-oxide synthase. Development of novel 4-oxo-pteridine antagonists of (6R)-5,6,7,8-tetrahydrobiopterin
J.Biol.Chem., 276:49133-49141, 2001

PubMed Abstract: Pathological nitric oxide (NO) generation in sepsis, inflammation, and stroke may be therapeutically controlled by inhibiting NO synthases (NOS). Here we targeted the (6R)-5,6,7,8-tetrahydro-l-biopterin (H(4)Bip)-binding site of NOS, which, upon cofactor binding, maximally increases enzyme activity and NO production from substrate l-arginine. The first generation of H(4)Bip-based NOS inhibitors employed a 4-amino pharmacophore of H(4)Bip analogous to antifolates such as methotrexate. We developed a novel series of 4-oxo-pteridine derivatives that were screened for inhibition against neuronal NOS (NOS-I) and a structure-activity relationship was determined. To understand the structural basis for pterin antagonism, selected derivatives were docked into the NOS pterin binding cavity. Using a reduced 4-oxo-pteridine scaffold, derivatives with certain modifications such as electron-rich aromatic phenyl or benzoyl groups at the 5- and 6-positions, were discovered to markedly inhibit NOS-I, possibly due to hydrophobic and electrostatic interactions with Phe(462) and Ser(104), respectively, within the pterin binding pocket. One of the most effective 4-oxo compounds and, for comparisons an active 4-amino derivative, were then co-crystallized with the endothelial NOS (NOS-III) oxygenase domain and this structure solved to confirm the hypothetical binding modes. Collectively, these findings suggest (i) that, unlike the antifolate principle, the 4-amino substituent is not essential for developing pterin-based NOS inhibitors and (ii), provide a steric and electrostatic basis for their rational design.

PubMed: 11590164
DOI: 10.1074/jbc.M011469200

Experimental method

X-RAY DIFFRACTION (1.9 Å)