PDBsum entry 1o0h

Hydrolase

PDB id: 1o0h

Contents

Protein chains

124 a.a. *

Ligands

ADP ×2

Waters ×541

* Residue conservation analysis

PDB id:

1o0h

Name:

Hydrolase

Title:

Ribonuclease a in complex with 5'-adp

Structure:

Ribonuclease pancreatic. Chain: a, b. Synonym: ribonuclease a. Ec: 3.1.27.5

Source:

Bos taurus. Cattle. Organism_taxid: 9913

Resolution:

1.20Å R-factor: 0.190 R-free: 0.221

Authors:

D.D.Leonidas,N.G.Oikonomakos,E.D.Chrysina,M.N.Kosmopoulou,M.Vlassi

Key ref:

D.D.Leonidas et al. (2003). High-resolution crystal structures of ribonuclease A complexed with adenylic and uridylic nucleotide inhibitors. Implications for structure-based design of ribonucleolytic inhibitors. Protein Sci, 12, 2559-2574. PubMed id: 14573867 DOI: 10.1110/ps.03196603

Date:

21-Feb-03 Release date: 09-Dec-03

Protein chains

P61823  (RNAS1_BOVIN) -  Ribonuclease pancreatic from Bos taurus

Seq: 150 a.a.

Struc: 124 a.a.

Enzyme reactions

• Enzyme class: E.C.4.6.1.18 - pancreatic ribonuclease.
• Reaction:
  1. an [RNA] containing cytidine + H2O = an [RNA]-3'-cytidine- 3'-phosphate + a 5'-hydroxy-ribonucleotide-3'-[RNA]
  2. an [RNA] containing uridine + H2O = an [RNA]-3'-uridine-3'-phosphate + a 5'-hydroxy-ribonucleotide-3'-[RNA]

DOI no: 10.1110/ps.03196603

Protein Sci 12:2559-2574 (2003)

PubMed id: 14573867

High-resolution crystal structures of ribonuclease A complexed with adenylic and uridylic nucleotide inhibitors. Implications for structure-based design of ribonucleolytic inhibitors.

D.D.Leonidas, G.B.Chavali, N.G.Oikonomakos, E.D.Chrysina, M.N.Kosmopoulou, M.Vlassi, C.Frankling, K.R.Acharya.

ABSTRACT

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.

Selected figure(s)

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.

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.

The above figures are reprinted by permission from the Protein Society: Protein Sci (2003, 12, 2559-2574) copyright 2003.

Figures were selected by an automated process.