Abstract
The Bürgi-Dunitz angle (αBD) describes the trajectory of approach of a nucleophile to an electrophile. The adoption of a stereoelectronically favorable αBD can necessitate significant reactive-group repositioning over the course of bond formation. In the context of enzyme catalysis, interactions with the protein constrain substrate rotation, which could necessitate structural transformations during bond formation. To probe this theoretical framework vis-à-vis biocatalysis, Schiff-base formation was analysed in Francisella tularensis trans-aldolase (TAL). Crystal structures of wild-type and Lys→Met mutant TAL in covalent and noncovalent complexes with fructose 6-phosphate and sedoheptulose 7-phosphate clarify the mechanism of catalysis and reveal that substrate keto moieties undergo significant conformational changes during Schiff-base formation. Structural changes compelled by the trajectory considerations discussed here bear relevance to bond formation in a variety of constrained enzymic/engineered systems and can inform the design of covalent therapeutics.
Original language | English (US) |
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Pages (from-to) | 544-552 |
Number of pages | 9 |
Journal | Acta Crystallographica Section D: Biological Crystallography |
Volume | 70 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2014 |
Keywords
- Bürgi-Dunitz angle
- Schiff bases
- imines
- induced fit
- nucleophiles
- pentose phosphate pathway
ASJC Scopus subject areas
- Structural Biology
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Dive into the research topics of 'Adherence to Bürgi-Dunitz stereochemical principles requires significant structural rearrangements in Schiff-base formation: Insights from transaldolase complexes'. Together they form a unique fingerprint.Datasets
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1.65 Angstrom Resolution Crystal Structure of Transaldolase B (TalA) from Francisella tularensis in Covalent Complex with Sedoheptulose-7-Phosphate
Light, S. H. (Contributor), Minasov, G. (Contributor), Duban, M.-E. (Contributor) & Anderson, W. F. (Contributor), Protein Data Bank (PDB), Sep 14 2011
DOI: 10.2210/pdb3TNO/pdb, https://www.wwpdb.org/pdb?id=pdb_00003tno
Dataset
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2.0 Angstrom Resolution Crystal Structure of Transaldolase B (TalA) from Francisella tularensis in Covalent Complex with Fructose 6-Phosphate
Light, S. H. (Contributor), Minasov, G. (Contributor), Duban, M.-E. (Contributor) & Anderson, W. F. (Contributor), Protein Data Bank (PDB), Sep 7 2011
DOI: 10.2210/pdb3TK7/pdb, https://www.wwpdb.org/pdb?id=pdb_00003tk7
Dataset
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1.8 Angstrom Resolution Crystal Structure of K135M Mutant of Transaldolase B (TalA) from Francisella tularensis in Complex with Fructose 6-phosphate
Light, S. H. (Contributor), Minasov, G. (Contributor), Duban, M.-E. (Contributor) & Anderson, W. F. (Contributor), Protein Data Bank (PDB), Aug 24 2011
DOI: 10.2210/pdb3TE9/pdb, https://www.wwpdb.org/pdb?id=pdb_00003te9
Dataset