1yci

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Revision as of 18:11, 12 November 2007

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spinqualitylabelsall models 1yci, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Factor inhibiting HIF-1 alpha in complex with N-(carboxycarbonyl)-D-phenylalanine

Overview

A set of four non-heme iron(II) and 2-oxoglutarate-dependent enzymes catalyze the post-translational modification of a transcription factor, hypoxia inducible factor (HIF), that mediates the hypoxic response in animals. Hydroxylation of HIF both causes its degradation and limits its activity. We describe how the use of structural data coupled to solid-phase synthesis led to the discovery of a selective inhibitor of one of the HIF hydroxylases. The inhibitor N-oxalyl-D-phenylalanine was shown to inhibit the HIF asparaginyl hydroxylase (FIH) but not a HIF prolyl hydroxylase. A crystal structure of the inhibitor complexed to FIH reveals that it binds in the 2OG and, likely, in the dioxygen binding site. The results will help to enable the modulation of the hypoxic response for the up-regulation of specific genes of biomedical importance, such as erythropoietin and vascular endothelial growth factor.

About this Structure

1YCI is a Single protein structure of sequence from Homo sapiens with FE2, SO4 and NDF as ligands. Active as Peptide-aspartate beta-dioxygenase, with EC number 1.14.11.16 Full crystallographic information is available from OCA.

Reference

Selective inhibition of factor inhibiting hypoxia-inducible factor., McDonough MA, McNeill LA, Tilliet M, Papamicael CA, Chen QY, Banerji B, Hewitson KS, Schofield CJ, J Am Chem Soc. 2005 Jun 1;127(21):7680-1. PMID:15913349

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