PDBsum entry 3d7b

Hydrolase

PDB id: 3d7b

Contents

Protein chains

124 a.a. *

Ligands

FLC ×2

U4S

Waters ×346

* Residue conservation analysis

PDB id:

3d7b

Name:

Hydrolase

Title:

The ribonuclease a- 5'-deoxy-5'-n-pyrrolidinouridine complex

Structure:

Ribonuclease pancreatic. Chain: a, b. Synonym: rnase 1, rnase a. Ec: 3.1.27.5

Source:

Bos taurus. Bovine. Organism_taxid: 9913

Resolution:

1.60Å R-factor: 0.180 R-free: 0.213

Authors:

D.D.Leonidas,S.E.Zographos,N.G.Oikonomakos

Key ref:

A.Samanta et al. (2009). Morpholino, piperidino, and pyrrolidino derivatives of pyrimidine nucleosides as inhibitors of ribonuclease A: synthesis, biochemical, and crystallographic evaluation. J Med Chem, 52, 932-942. PubMed id: 19173562

Date:

21-May-08 Release date: 10-Feb-09

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]

J Med Chem 52:932-942 (2009)

PubMed id: 19173562

Morpholino, piperidino, and pyrrolidino derivatives of pyrimidine nucleosides as inhibitors of ribonuclease A: synthesis, biochemical, and crystallographic evaluation.

A.Samanta, D.D.Leonidas, S.Dasgupta, T.Pathak, S.E.Zographos, N.G.Oikonomakos.

ABSTRACT

Six 5'-deoxy-5'-morpholine, piperidine, and pyrrolidine of pyrimidine nucleosides have been synthesized and characterized. Their inhibitory action to ribonuclease A has been studied by biochemical analysis and X-ray crystallography. These compounds are moderate inhibitors of RNase A with mid-to-upper micromolar inhibition constants (K(i)). The high resolution X-ray crystal structures of the RNase A-inhibitor complexes have shown that all inhibitors bind at the enzyme catalytic cleft with the pyrimidine nucleobase at the B(1)R(2) subsites while the 5' group binds away from the main subsite P(1), where P-O(5') bond cleavage occurs, toward the solvent close to subsite P(0). Structure-activity relationship analysis has demonstrated that the compounds with the larger group in the 5' position are more potent. Comparative structural analysis of these RNase A complexes with other similar RNase A-ligand complexes provides a structural explanation of their potency and suggests ways to improve their efficiency and selectivity. These inhibitors can be the starting point for the development of compounds that can be used as pharmaceuticals against pathologies associated with RNase A homologues such as human angiogenin, which is implicated in tumor induced neovascularization.