Hypoxia-Inducible factor 1 alpha inhibitor

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Structure of human pentameric SAP (green, grey, pink, yellow, magenta) complex with AMP and Ca+2 ions (green) (PDB code 1lgn)

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Function

Hypoxia-Inducible factor 1 alpha inhibitor (FIH-1) is an inhibitor of Hypoxia-Inducible Factors 1 alpha (HIF-1). HIF-1 is a master regulator of oxygen homeostasis via transcription activation. Thus, FIH-1 is an inhibitor of transcriptional activation ^[1]. FIH-1 is an oxygen-dependent asparagine Hydroxylase ^[2].

Relevance

Mutations in SAP affect the aggregation of mutated lysozyme which cause amyloidosis. The inhibition of SAP binding to amyloid fibrils is a therapeutic target in some serious human diseases^[3]. Small molecule ligands can displace SAP from amyloid fibrils and can provide therapeutic treatment of amyloidosis.

Structural highlights

 ^[4].

3D Structures of Hypoxia-Inducible factor 1 alpha inhibitor

Updated on 23-February-2021

References

↑ Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 2001 Oct 15;15(20):2675-86. PMID:11641274 doi:http://dx.doi.org/10.1101/gad.924501
↑ Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 2002 Jun 15;16(12):1466-71. PMID:12080085 doi:10.1101/gad.991402
↑ Richards DB, Cookson LM, Berges AC, Barton SV, Lane T, Ritter JM, Fontana M, Moon JC, Pinzani M, Gillmore JD, Hawkins PN, Pepys MB. Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component. N Engl J Med. 2015 Sep 17;373(12):1106-14. doi: 10.1056/NEJMoa1504942. Epub 2015 , Jul 15. PMID:26176329 doi:http://dx.doi.org/10.1056/NEJMoa1504942
↑ Hohenester E, Hutchinson WL, Pepys MB, Wood SP. Crystal structure of a decameric complex of human serum amyloid P component with bound dAMP. J Mol Biol. 1997 Jun 20;269(4):570-8. PMID:9217261 doi:10.1006/jmbi.1997.1075