RT Journal Article SR Electronic T1 Steric Mapping of the L-Methionine Binding Site of ATP:L-Methionine S-Adenosyltransferase JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 307 OP 313 VO 19 IS 2 A1 JANICE R. SUFRIN A1 DEBORAH A. DUNN A1 GARLAND R. MARSHALL YR 1981 UL http://molpharm.aspetjournals.org/content/19/2/307.abstract AB Three-dimensional steric mapping of the L-methionine binding site of mammalian (rat liver) ATP:L-methionine S-adenosyltransferase (EC 2.5.1.6) has been accomplished by computing the combined occupied volume of six inhibitory, conformationally rigid, amino acid analogues that have been shown in previous studies, which used an enzyme preparation of undetermined isozymic composition, to bind to the enzyme surface in competition with L-methionine. [Coulter, A. W., J. B. Lombardini, J. R. Sufrin, and P. Talalay. Mol. Pharmacol. 10:319-334 (1974); Sufrin, J. R., A. W. Coulter, and P. Talalay. Mol. Pharmacol. 15:661-677 (1979).] These six amino acids, all of which are derivatives of 1-aminocyclopentane-1-carboxylic acid, include (1R,2R,4S)-2-aminonorbornane-2-carboxylic acid, (1S,2S,4R)-2-aminonorbornane-2-carboxylic acid, (1R,2S,4S)-2-aminonorbornane-2-carboxylic acid, (1R,2R,4S)-2-amino-5,6-exo-trimethylenenorbornane-2-carboxylic acid, 7-aminonorbornane-7-carboxylic acid, and 9-aminofluorene-9-carboxylic acid. This has generated an "enzyme-excluded" volume map, which defines that region of the active site known to be available for binding by substrates or inhibitors structurally related to L-methionine. Volume mapping of three conformationally rigid analogues which possess the minimal structural requirements for recognition, but nevertheless are inactive, has been carried out to determine their unique volume requirements that are not associated with the enzyme-excluded volume. These inactive amino acids are (1S,2R,4R)-2-aminonorbornane-2-carboxylic acid, (1R,2R,4S)-2-aminobicyclo[3.2.1]octane-2-carboxylic acid, and 2-aminoadamantane-2-carboxylic acid. Intersection of the unique volume segments of the three inactive analogues shows one region of unique volume overlap for all three molecules and defines an "enzyme-essential" region, i.e., a region required by the enzyme itself and not available for ligand binding. ACKNOWLEDGMENTS We would like to express our appreciation to Dr. Paul Talalay, who initiated the cited studies on methionine analogue inhibitors of isofunctional methionine adenosyltransferases, and to Dr. Christine Humblet for assisting in the construction of several molecules for the computer mapping determinations.