title: A path from primary protein sequence to ligand recognition.
abstract: A novel method to organize protein structural information based solely on sequence is presented. The method clusters proteins into families that correlate with the three-dimensional protein structure and the conformation of the bound ligands. This procedure was applied to nicotinamide adenine dinucleotide [NAD(P)]-utilizing enzymes to identify a total of 94 sequence families, 53 of which are structurally characterized. Each of the structurally characterized proteins within a sequence family correlates to a single protein fold and to a common bound conformation of NAD(P). A wide range of structural folds is identified that recognize NAD(P), including Rossmann folds and beta/alpha barrels. The defined sequence families can be used to identify the type and prevalence of NAD(P)-utilizing enzymes in the proteomes of sequenced organisms. The proteome of Mycobacterium tuberculosis was mined to generate a proteome-wide profile of NAD(P)-utilizing enzymes coded by this organism. This enzyme family comprises approximately 6% of the open reading frames, with the largest subgroup being the Rossmann fold, short-chain dehydrogenases. The preponderance of short-chain dehydrogenases correlates strongly with the phenotype of M. tuberculosis, which is characterized as having one of the most complex prokaryotic cell walls.
authors.affiliation: Triad Therapeutics, Inc., San Diego, CA 92121, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Kho
authors.forename: Brian L
authors.initials: BL
authors.lastname: Baker
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Newman
authors.forename: Richard M
authors.initials: RM
authors.lastname: Jack
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Sem
authors.forename: Hugo O
authors.initials: HO
authors.lastname: Villar
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hansen
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D016000:Cluster Analysis; D004798:Enzymes / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D005415:Flavins / Q000378:metabolism; D005787:Gene Frequency; D016680:Genome, Bacterial; D008024:Ligands; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology / Q000235:genetics; D009249:NADP / Q000737:chemistry / Q000378:metabolism*; D009252:NADPH Dehydrogenase / Q000737:chemistry; D010088:Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry / Q000145:classification / Q000378:metabolism; D020543:Proteome / Q000032:analysis; D020539:Sequence Analysis, Protein / Q000379:methods*
chemical_list: D001426:Bacterial Proteins; D004798:Enzymes; D005415:Flavins; D008024:Ligands; D011506:Proteins; D020543:Proteome; D009249:NADP; D010088:Oxidoreductases; D009252:NADPH Dehydrogenase