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The 1.9 Å Crystal Structure of Alanine Racemase from Mycobacterium tuberculosis Contains a Conserved Entryway into the Active Site†,‡
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and Kurt L. Krause*§@
Section:Abstract
We report the crystal structure of alanine racemase from Mycobacterium tuberculosis (AlrMtb) at 1.9 Å resolution. In our structure, AlrMtb is found to be a dimer formed by two crystallographically different monomers, each comprising 384 residues. The domain makeup of each monomer is similar to that of Bacillus and Pseudomonas alanine racemases and includes both an α/β-barrel at the N-terminus and a C-terminus primarily made of β-strands. The hinge angle between these two domains is unique for AlrMtb, but the active site geometry is conserved. In AlrMtb, the PLP cofactor is covalently bound to the protein via an internal aldimine bond with Lys42. No guest substrate is noted in its active site, although some residual electron density is observed in the enzyme's active site pocket. Analysis of the active site pocket, in the context of other known alanine racemases, allows us to propose the inclusion of conserved residues found at the entrance to the binding pocket as additional targets in ongoing structure-aided drug design efforts. Also, as observed in other alanine racemase structures, PLP adopts a conformation that significantly distorts the planarity of the extended conjugated system between the PLP ring and the internal aldimine bond.
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This article has been cited by 2 ACS Journal articles (2 most recent appear below).
Drug Discovery Targeting Amino Acid Racemases
Paola Conti, Lucia Tamborini, Andrea Pinto, Arnaud Blondel, Paola Minoprio, Andrea Mozzarelli, and Carlo De MicheliChemical Reviews2011 111 (11), 6919-6946Drug Discovery Targeting Amino Acid Racemases
Paola Conti, Lucia Tamborini, Andrea Pinto, Arnaud Blondel, Paola Minoprio, Andrea Mozzarelli, and Carlo De MicheliChemical Reviews2011 111 (11), 6919-6946
A Combined Quantum Mechanical and Molecular Mechanical Study of the Reaction Mechanism and α-Amino Acidity in Alanine Racemase
Dan Thomas Major and Jiali GaoJournal of the American Chemical Society2006 128 (50), 16345-16357A Combined Quantum Mechanical and Molecular Mechanical Study of the Reaction Mechanism and α-Amino Acidity in Alanine Racemase
Dan Thomas Major and Jiali GaoJournal of the American Chemical Society2006 128 (50), 16345-16357Combined quantum mechanical/molecular mechanical simulations have been carried out to investigate the origin of the carbon acidity enhancement in the alanine racemization reaction catalyzed by alanine racemase (AlaR). The present study shows that the ...
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History
- Published In Issue February 08, 2005
- Received June 27, 2004
Revised Manuscript Received October 22, 2004
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