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PDBsum entry 2bwk
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References listed in PDB file
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Key reference
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Title
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Structure of murine angiogenin: features of the substrate- And cell-Binding regions and prospects for inhibitor-Binding studies.
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Authors
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D.E.Holloway,
G.B.Chavali,
M.C.Hares,
V.Subramanian,
K.R.Acharya.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2005,
61,
1568-1578.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 4.
Hydrophobic packing of the C-terminus. (a) and (c), mAng-SO[4]. (b) and (d), hAng (PDB
code 1b1i ; Leonidas, Shapiro, Allen et al., 1999 [Leonidas, D. D., Shapiro, R.,
Allen, S. C., Subbarao, G. V., Veluraja, K. & Acharya, K. R. (1999). J. Mol. Biol. 285,
1209-1233.]-[bluearr.gif] ). Hybrid representation in which secondary structures
(grey) are shown in schematic form and side chains of C-terminal hydrophobic residues
(gold), the pocket base (blue) and collar (red) are shown in both ball-and-stick and
opaque space-filling forms. mAng Met70 is modelled in dual conformation. (c) and (d) were
obtained from (a) and (b), respectively, by a 90° rotation about the x axis.
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Figure 6.
Packing of mAng-PO[4] crystals. (a) Transverse section through a solvent channel. (b)
Details of the interactions between the C-terminus and symmetry-related neighbours SYM MOL
1 and SYM MOL 2 (see text for details). Shown are mAng (residues 2-114 in red, residues
115-119 in gold), a superposed pdUppA-3'-p molecule obtained by alignment of the
mAng-PO[4]monomer with the RNase A-pdUppA-3'-p complex (PDB code 1qhc ; Leonidas,
Shapiro, Irons et al., 1999 [Leonidas, D. D., Shapiro, R., Irons, L. I., Russo, N. &
Acharya, K. R. (1999). Biochemistry, 32, 10287-10297.]-[bluearr.gif] ; blue) and
selected symmetry-related neighbours (grey/black). The side chains of Lys19, Arg24 and
Arg28 are disordered beyond C^ [beta] .
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The above figures are
reprinted
by permission from the IUCr:
Acta Crystallogr D Biol Crystallogr
(2005,
61,
1568-1578)
copyright 2005.
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