1b1i
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CRYSTAL STRUCTURE OF HUMAN ANGIOGENIN
OverviewOverview
Human angiogenin (Ang), an unusual member of the pancreatic RNase, superfamily, is a potent inducer of angiogenesis in vivo. Its, ribonucleolytic activity is weak (10(4) to 10(6)-fold lower than that of, bovine RNase A), but nonetheless seems to be essential for biological, function. Ang has been implicated in the establishment of a wide range of, human tumours and has therefore emerged as an important target for the, design of new anti-cancer compounds. We report high-resolution crystal, structures for native Ang in two different forms (Pyr1 at 1.8 A and Met-1, at 2.0 A resolution) and for two active-site variants, K40Q and H13A, at, 2.0 A resolution. The native structures, together with earlier mutational, and biochemical data, provide a basis for understanding the unique, functional properties of this molecule. The major structural features that, underlie the weakness of angiogenin's RNase activity include: (i) the, obstruction of the pyrimidine-binding site by Gln117; (ii) the existence, of a hydrogen bond between Thr44 and Thr80 that further suppresses the, effectiveness of the pyrimidine site; (iii) the absence of a counterpart, for the His119-Asp121 hydrogen bond that potentiates catalysis in RNase A, (the corresponding aspartate in Ang, Asp116, has been recruited to, stabilise the blockage of the pyrimidine site); and (iv) the absence of, any precise structural counterparts for two important purine-binding, residues of RNase A. Analysis of the native structures has revealed, details of the cell-binding region and nuclear localisation signal of Ang, that are critical for angiogenicity. The cell-binding site differs, dramatically from the corresponding regions of RNase A and two other, homologues, eosinophil-derived neurotoxin and onconase, all of which lack, angiogenic activity. Determination of the structures of the catalytically, inactive variants K40Q and H13A has now allowed a rigorous assessment of, the relationship between the ribonucleolytic and biological activities of, Ang. No significant change outside the enzymatic active site was observed, in K40Q, establishing that the loss of angiogenic activity for this, derivative is directly attributable to disruption of the catalytic, apparatus. The H13A structure shows some changes beyond the, ribonucleolytic site, but sites involved in cell-binding and nuclear, translocation are essentially unaffected by the amino acid replacement.
DiseaseDisease
Known diseases associated with this structure: Amyotrophic lateral sclerosis, susceptibility to OMIM:[105850]
About this StructureAbout this Structure
1B1I is a Single protein structure of sequence from Homo sapiens with CIT as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Refined crystal structures of native human angiogenin and two active site variants: implications for the unique functional properties of an enzyme involved in neovascularisation during tumour growth., Leonidas DD, Shapiro R, Allen SC, Subbarao GV, Veluraja K, Acharya KR, J Mol Biol. 1999 Jan 22;285(3):1209-33. PMID:9918722
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