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At least 235 records · Page 13Linked to original sources
PubMed1995

Modular structure of neuronal nitric oxide synthase: localization of the arginine binding site and modulation by pterin.

A putative dihydrofolate reductase (DHFR) module has been identified in neuronal nitric oxide synthase, consisting of amino acids 558-721, and is proposed to be the site of tetrahydrobiopterin (BH4) binding. This polypeptide has been expressed in E. coli as a fusion protein with glutathione S-transferase (GST), using the plasmid pGEX-4T1. The protein binds N omega-nitro-L-arginine (NNA) tightly, but this binding is not stimulated by BH4. cDNAs for Module II (residues 220-557) and Module III (residues 220-721) have been expressed as fusion proteins with GST. Module II does not bind NNA. However, Module III does bind NNA and binding is significantly stimulated by BH4. These observations are taken as strong evidence that the DHFR module contains the L-arginine binding site and, presumably, the BH4 binding site by analogy to its homology with DHFR, but that tight binding of BH4 requires amino acids 220-577.

Amino Acid Oxidoreductases↗
PubMed1993

Computer-aided drug design: a free energy perturbation study on the binding of methyl-substituted pterins and N5-deazapterins to dihydrofolate reductase.

Molecular dynamics simulation and free energy perturbation techniques have been used to study the relative binding free energies of 8-methylpterins and 8-methyl-N5-deazapterins to dihydrofolate reductase (DHFR). Methyl-substitution at the 5, 6 and 7 positions in the N-heterocyclic ring gives rise to a variety of ring substituent patterns and biological activity: several of these methyl derivatives of the 8-methyl parent compounds (8-methylpterin and 8-methyl-N5-deazapterin) have been identified as substrates or inhibitors of vertebrate DHFR in previous work. The calculated free energy differences reveal that the methyl-substituted compounds are thermodynamically more stable than the primary compounds (8-methylpterin and 8-methyl-N5-deazapterin) when bound to the enzyme, due largely to hydrophobic hydration phenomena. Methyl substitution at the 5 and/or 7 positions in the 6-methyl-substituted compounds has only a small effect on the stability of ligand binding. Furthermore, repulsive interactions between the 6-methyl substituent and DHFR are minimal, suggesting that the 6-methyl position is optimal for binding. The results also show that similarly substituted 8-methylpterins and 8-methyl-N5-deazapterins have very similar affinities for binding to DHFR. The computer simulation predictions are in broad agreement with experimental data obtained from kinetic studies, i.e. 6,8-dimethylpterin is a more efficient substrate than 8-methylpterin and 6,8-dimethyl-N5-deazapterin is a better inhibitor than 8-methyl-N5-deazapterin.

Animals↗