title: Computational design of an enzyme catalyst for a stereoselective bimolecular Diels-Alder reaction.
abstract: The Diels-Alder reaction is a cornerstone in organic synthesis, forming two carbon-carbon bonds and up to four new stereogenic centers in one step. No naturally occurring enzymes have been shown to catalyze bimolecular Diels-Alder reactions. We describe the de novo computational design and experimental characterization of enzymes catalyzing a bimolecular Diels-Alder reaction with high stereoselectivity and substrate specificity. X-ray crystallography confirms that the structure matches the design for the most active of the enzymes, and binding site substitutions reprogram the substrate specificity. Designed stereoselective catalysts for carbon-carbon bond-forming reactions should be broadly useful in synthetic chemistry.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Justin B
authors.initials: JB
authors.lastname: Siegel
authors.forename: Alexandre
authors.initials: A
authors.lastname: Zanghellini
authors.forename: Helena M
authors.initials: HM
authors.lastname: Lovick
authors.forename: Gert
authors.initials: G
authors.lastname: Kiss
authors.forename: Abigail R
authors.initials: AR
authors.lastname: Lambert
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: St Clair
authors.forename: Jasmine L
authors.initials: JL
authors.lastname: Gallaher
authors.forename: Donald
authors.initials: D
authors.lastname: Hilvert
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.forename: Barry L
authors.initials: BL
authors.lastname: Stoddard
authors.forename: Kendall N
authors.initials: KN
authors.lastname: Houk
authors.forename: Forrest E
authors.initials: FE
authors.lastname: Michael
authors.forename: David
authors.initials: D
authors.lastname: Baker
mesh_terms: D000178:Acrylamides / Q000737:chemistry; D000465:Algorithms; D002070:Butadienes / Q000737:chemistry; D002244:Carbon / Q000737:chemistry*; D002384:Catalysis; D020134:Catalytic Domain; D055598:Chemical Phenomena; D003198:Computer Simulation; D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D004798:Enzymes / Q000737:chemistry* / Q000235:genetics; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008958:Models, Molecular; D016296:Mutagenesis; D011487:Protein Conformation; D015202:Protein Engineering; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D012984:Software; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: C551201:4-carboxybenzyl trans-1,3-butadiene-1-carbamate; D000178:Acrylamides; D002070:Butadienes; D004798:Enzymes; D011506:Proteins; D002244:Carbon; C099046:N,N-dimethylacrylamide