title: Target selection and annotation for the structural genomics of the amidohydrolase and enolase superfamilies.
abstract: To study the substrate specificity of enzymes, we use the amidohydrolase and enolase superfamilies as model systems; members of these superfamilies share a common TIM barrel fold and catalyze a wide range of chemical reactions. Here, we describe a collaboration between the Enzyme Specificity Consortium (ENSPEC) and the New York SGX Research Center for Structural Genomics (NYSGXRC) that aims to maximize the structural coverage of the amidohydrolase and enolase superfamilies. Using sequence- and structure-based protein comparisons, we first selected 535 target proteins from a variety of genomes for high-throughput structure determination by X-ray crystallography; 63 of these targets were not previously annotated as superfamily members. To date, 20 unique amidohydrolase and 41 unique enolase structures have been determined, increasing the fraction of sequences in the two superfamilies that can be modeled based on at least 30% sequence identity from 45% to 73%. We present case studies of proteins related to uronate isomerase (an amidohydrolase superfamily member) and mandelate racemase (an enolase superfamily member), to illustrate how this structure-focused approach can be used to generate hypotheses about sequence-structure-function relationships.
authors.affiliation: Department of Biopharmaceutical Sciences, California Institute for Quantitative Biosciences, University of California at San Francisco, San Francisco, CA 94158, USA. ursula@salilab.org
authors.forename: Ursula
authors.initials: U
authors.lastname: Pieper
authors.forename: Ranyee
authors.initials: R
authors.lastname: Chiang
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Seffernick
authors.forename: Shoshana D
authors.initials: SD
authors.lastname: Brown
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Glasner
authors.forename: Libusha
authors.initials: L
authors.lastname: Kelly
authors.forename: Narayanan
authors.initials: N
authors.lastname: Eswar
authors.forename: J Michael
authors.initials: JM
authors.lastname: Sauder
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Bonanno
authors.forename: Subramanyam
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Burley
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zheng
authors.forename: Mark R
authors.initials: MR
authors.lastname: Chance
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.forename: John A
authors.initials: JA
authors.lastname: Gerlt
authors.forename: Frank M
authors.initials: FM
authors.lastname: Raushel
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Jacobson
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Babbitt
authors.forename: Andrej
authors.initials: A
authors.lastname: Sali
mesh_terms: D000581:Amidohydrolases / Q000737:chemistry*; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D030562:Databases, Protein; D023281:Genomics / Q000379:methods*; D010751:Phosphopyruvate Hydratase / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D013379:Substrate Specificity
chemical_list: D000581:Amidohydrolases; D010751:Phosphopyruvate Hydratase