3P3P

Factor inhibiting HIF-1 Alpha in complex with Notch 1 fragment mouse notch (1997-2016) peptide

Summary for 3P3P

• Entry DOI: 10.2210/pdb3p3p/pdb
• Related: 1H2K 1H2L 1H2M 2QC9 2ZGD 3D8C 3P3N
• Descriptor: Hypoxia-inducible factor 1-alpha inhibitor, Notch 1 protein, FE (II) ION, ... (7 entities in total)
• Functional Keywords: double stranded beta-helix, hydroxylase, iron binding, 2-oxoglutarate binding, hypoxia inducible factor binding, ankyrin repeat domain binding, oxidoreductase-transcription complex, oxidoreductase/transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus (Potential): Q9NWT6
• Total number of polymer chains: 2
• Total formula weight: 42927.68

Authors

McDonough, M.A.,Schofield, C.J. (deposition date: 2010-10-05, release date: 2010-11-24, Last modification date: 2024-02-21)

Primary citation

Coleman, M.L.,Mcdonough, M.A.,Hewitson, K.S.,Coles, C.,Mecinovic, J.,Edelmann, M.,Cook, K.M.,Cockman, M.E.,Lancaster, D.E.,Kessler, B.M.,Oldham, N.J.,Ratcliffe, P.J.,Schofield, C.J.
Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor
J.Biol.Chem., 282:24027-24038, 2007

PubMed Abstract: The stability and activity of hypoxia-inducible factor (HIF) are regulated by the post-translational hydroxylation of specific prolyl and asparaginyl residues. We show that the HIF asparaginyl hydroxylase, factor inhibiting HIF (FIH), also catalyzes hydroxylation of highly conserved asparaginyl residues within ankyrin repeat (AR) domains (ARDs) of endogenous Notch receptors. AR hydroxylation decreases the extent of ARD binding to FIH while not affecting signaling through the canonical Notch pathway. ARD proteins were found to efficiently compete with HIF for FIH-dependent hydroxylation. Crystallographic analyses of the hydroxylated Notch ARD (2.35A) and of Notch peptides bound to FIH (2.4-2.6A) reveal the stereochemistry of hydroxylation on the AR and imply that significant conformational changes are required in the ARD fold in order to enable hydroxylation at the FIH active site. We propose that ARD proteins function as natural inhibitors of FIH and that the hydroxylation status of these proteins provides another oxygen-dependent interface that modulates HIF signaling.

PubMed: 17573339

Experimental method

X-RAY DIFFRACTION (2.6 Å)