Structure of murine angiogenin: features of the substrate- and cell-binding regions and prospects for inhibitor-binding studies.
Angiogenin is an unusual member of the pancreatic ribonuclease superfamily that induces blood-vessel formation and is a promising anticancer target. The three-dimensional structure of murine angiogenin (mAng) has been determined by X-ray crystallography. Two structures are presented: one is a complex with sulfate ions (1.5 Angstroms resolution) and the other a complex with phosphate ions (1.6 Angstroms resolution). Residues forming the putative B(1), P(1) and B(2) subsites occupy positions similar to their hAng counterparts and are likely to play similar roles. The anions occupy the P(1) subsite, sulfate binding conventionally and phosphate adopting two orientations, one of which is novel. The B(1) subsite is obstructed by Glu116 and Phe119, with the latter assuming a less invasive position than its hAng counterpart. Hydrophobic interactions between the C-terminal segment and the main body of the protein are more extensive than in hAng and may underly the lower enzymatic activity of the murine protein. Elsewhere, the structure of the H3-B2 loop supports the view that hAng Asn61 interacts directly with cell-surface molecules and does not merely stabilize adjacent regions of the hAng structure. mAng crystals appear to offer small-molecule inhibitors a clear route to the active site and may even withstand a reorientation of the C-terminal segment that provides access to the cryptic B(1) subsite. These features represent considerable advantages over crystalline hAng and bAng.
Holloway
Daniel E
DE
Department of Biology and Biochemistry, University of Bath, England.
Chavali
Gayatri B
GB
Hares
Michelle C
MC
Subramanian
Vasanta
V
Acharya
K Ravi
KR
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D003460:Crystallization; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D012259:Ribonuclease, Pancreatic / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D016415:Sequence Alignment
C046366:angiogenin; D012259:Ribonuclease, Pancreatic