3N59: Type Ii Dehydroquinase From Mycobacterium Tuberculosis Complexed With 3-Dehydroshikimate

Citation:
Abstract
The shikimate pathway is essential in Mycobacterium tuberculosis and its absence from humans makes the enzymes of this pathway potential drug targets. In the present paper, we provide structural insights into ligand and inhibitor binding to 3-dehydroquinate dehydratase (dehydroquinase) from M. tuberculosis (MtDHQase), the third enzyme of the shikimate pathway. The enzyme has been crystallized in complex with its reaction product, 3-dehydroshikimate, and with six different competitive inhibitors. The inhibitor 2,3-anhydroquinate mimics the flattened enol/enolate reaction intermediate and serves as an anchor molecule for four of the inhibitors investigated. MtDHQase also forms a complex with citrazinic acid, a planar analogue of the reaction product. The structure of MtDHQase in complex with a 2,3-anhydroquinate moiety attached to a biaryl group shows that this group extends to an active-site subpocket inducing significant structural rearrangement. The flexible extensions of inhibitors designed to form pi-stacking interactions with the catalytic Tyr24 have been investigated. The high-resolution crystal structures of the MtDHQase complexes provide structural evidence for the role of the loop residues 19-24 in MtDHQase ligand binding and catalytic mechanism and provide a rationale for the design and efficacy of inhibitors.
PDB ID: 3N59Download
MMDB ID: 83524
PDB Deposition Date: 2010/5/24
Updated in MMDB: 2010/07
Experimental Method:
x-ray diffraction
Resolution: 2.52  Å
Source Organism:
Similar Structures:
Biological Unit for 3N59: dodecameric; determined by author and by software (PISA)
Molecular Components in 3N59
Label Count Molecule
Proteins (12 molecules)
12
3-dehydroquinate Dehydratase
Molecule annotation
Chemicals (14 molecules)
1
12
2
2
* Click molecule labels to explore molecular sequence information.

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