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PDBsum entry 1o0h
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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High-Resolution crystal structures of ribonuclease a complexed with adenylic and uridylic nucleotide inhibitors. Implications for structure-Based design of ribonucleolytic inhibitors.
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Authors
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D.D.Leonidas,
G.B.Chavali,
N.G.Oikonomakos,
E.D.Chrysina,
M.N.Kosmopoulou,
M.Vlassi,
C.Frankling,
K.R.Acharya.
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Ref.
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Protein Sci, 2003,
12,
2559-2574.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structures of bovine pancreatic ribonuclease A (RNase A) in complex
with 3',5'-ADP, 2',5'-ADP, 5'-ADP, U-2'-p and U-3'-p have been determined at
high resolution. The structures reveal that each inhibitor binds differently in
the RNase A active site by anchoring a phosphate group in subsite P1. The most
potent inhibitor of all five, 5'-ADP (Ki = 1.2 microM), adopts a syn
conformation (in contrast to 3',5'-ADP and 2',5'-ADP, which adopt an anti), and
it is the beta- rather than the alpha-phosphate group that binds to P1.
3',5'-ADP binds with the 5'-phosphate group in P1 and the adenosine in the B2
pocket. Two different binding modes are observed in the two RNase A molecules of
the asymmetric unit for 2',5'-ADP. This inhibitor binds with either the 3' or
the 5' phosphate groups in subsite P1, and in each case, the adenosine binds in
two different positions within the B2 subsite. The two uridilyl inhibitors bind
similarly with the uridine moiety in the B1 subsite but the placement of a
different phosphate group in P1 (2' versus 3') has significant implications on
their potency against RNase A. Comparative structural analysis of the RNase A,
eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), and
human angiogenin (Ang) complexes with these and other phosphonucleotide
inhibitors provides a wealth of information for structure-based design of
inhibitors specific for each RNase. These inhibitors could be developed to
therapeutic agents that could control the biological activities of EDN, ECP, and
ANG, which play key roles in human pathologies.
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Figure 2.
Figure 2. (A, B, D, E, and F) Diagrams of the interactions
between RNase A molecule I of the asymmetric unit and 3',5'-ADP,
2',5'-ADP, 5'-ADP, 2' UMP, and 3' UMP, respectively. (C) Diagram
of the interactions between RNase A and 2',5'-ADP in molecule II
of the asymmetric unit. Molecules I and II refer to the two
RNase A molecules in the asymmetric unit. Residues are drawn as
ball-and-stick models and water molecules as white spheres.
Hydrogen bonds are indicated as dashed lines.
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Figure 5.
Figure 5. A schematic representation of RNase A in complex
with 3',5'-ADP (in green). The inhibitors 2',5'-ADP (in gray and
cyan from molecules I and II of the asymmetric unit,
respectively), 5'-ADP (in red), U-3'-p (in magenta) and U-2'-p
(in yellow) are also shown.
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The above figures are
reprinted
by permission from the Protein Society:
Protein Sci
(2003,
12,
2559-2574)
copyright 2003.
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