PDBsum entry 2cl5

Transferase

PDB id: 2cl5

Contents

Protein chains

215 a.a.

Ligands

SAM ×2

BIE ×2

BU3 ×3

MES

Metals

_MG ×2

Waters ×554

References listed in PDB file

Key reference

• Title: Comparative study of ortho- And meta-Nitrated inhibitors of catechol-O-Methyltransferase: interactions with the active site and regioselectivity of o-Methylation.
• Authors: P.N.Palma, M.L.Rodrigues, M.Archer, M.J.Bonifácio, A.I.Loureiro, D.A.Learmonth, M.A.Carrondo, P.Soares-Da-Silva.
• Ref.: Mol Pharmacol, 2006, 70, 143-153.
• PubMed id: 16618795

Abstract

In this work, we present a comparative case study of "ortho-" and "meta-nitrated" catecholic inhibitors of catechol-O-methyltransferase (COMT), with regard to their interaction with the catalytic site of the enzyme and the in vitro regioselective formation of their mono-O-methyl ether metabolites. In particular, the effects of altering the attachment position of the inhibitors' side-chain substituent, within the classic nitrocatechol pharmacophore, were investigated. For this purpose, we compared two simple regioisomeric nitrocatechol-type inhibitors of COMT, BIA 3-228 and BIA 8-176, which contain the benzoyl substituent attached at the meta and ortho positions, respectively, relative to the nitro group. The two compounds were slowly O-methylated by COMT in vitro, but the particular substitution pattern of each compound was shown to have a profound impact on the regioselectivity of their O-methylation. To provide a plausible interpretation of these results, a comprehensive analysis of the protein-inhibitor interactions and of the relative chemical susceptibility to O-methylation of the catechol hydroxyl groups was performed by means of docking simulations and ab initio molecular orbital calculations. The major structural and chemical factors that determine the enzyme regioselectivity of O-methylation were identified, and the X-ray structure of the complex of COMT with S-adenosyl-l-methionine and BIA 8-176 is herein disclosed. This is the first reported structure of the soluble form of COMT complexed with a nitrocatecholic inhibitor having a bulky substituent group in adjacent position (ortho) to the nitro group. Structural and dynamic aspects of this complex are analyzed and discussed, in the context of the present study.

Secondary reference #1

• Title: Crystallization and preliminary X-Ray diffraction studies of a catechol-O-Methyltransferase/inhibitor complex.
• Authors: M.L.Rodrigues, M.J.Bonifácio, P.Soares-Da-Silva, M.A.Carrondo, M.Archer.
• Ref.: Acta Crystallograph Sect F Struct Biol Cryst Commun, 2005, 61, 118-120. [DOI no: 10.1107/S1744309104031197]
• PubMed id: 16508109

Figure 1.
Figure 1 Crystal of the recombinant S-COMT complexed with its cosubstrate, SAM, and the yellow inhibitor BIA 8-176. Its largest dimension is approximately 0.2 mm.

The above figure is reproduced from the cited reference which is an Open Access publication published by the IUCr