3N87

Crystal structure of 3-dehydroquinate dehydratase from Mycobacterium tuberculosis in complex with inhibitor 3

Summary for 3N87

• Entry DOI: 10.2210/pdb3n87/pdb
• Related: 3N76 3N7A 3N86 3N8N
• Descriptor: 3-dehydroquinate dehydratase, (1R,4R,5R)-1,4,5-trihydroxy-3-[3-(phenylcarbonyl)phenyl]cyclohex-2-ene-1-carboxylic acid (3 entities in total)
• Functional Keywords: dehydroquinate dehydratase, arod, shikimate pathway, mycobacterium tuberculosis, drug discovery, lyase, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 24
• Total formula weight: 387894.84

Authors

Dias, M.V.B.,Snee, W.C.,Bromfield, K.M.,Payne, R.,Palaninathan, S.K.,Ciulli, A.,Howard, N.I.,Abell, C.,Sacchettini, J.C.,Blundell, T.L. (deposition date: 2010-05-27, release date: 2011-05-11, Last modification date: 2024-02-21)

Primary citation

Dias, M.V.,Snee, W.C.,Bromfield, K.M.,Payne, R.J.,Palaninathan, S.K.,Ciulli, A.,Howard, N.I.,Abell, C.,Sacchettini, J.C.,Blundell, T.L.
Structural investigation of inhibitor designs targeting 3-dehydroquinate dehydratase from the shikimate pathway of Mycobacterium tuberculosis.
Biochem.J., 436:729-739, 2011

PubMed 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 π-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.

PubMed: 21410435
DOI: 10.1042/BJ20110002

Experimental method

X-RAY DIFFRACTION (2.4 Å)