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Structural investigation of inhibitor designs targeting 3-dehydroquinate dehydratase from the shikimate pathway of Mycobacterium tuberculosis.

Dias MV, Snee WC, Bromfield KM, Payne RJ, Palaninathan SK, Ciulli A, Howard NI, Abell C, Sacchettini JC, Blundell TL
Biochem J 436 729-39 (2011)
Related entries: 3n59, 3n7a, 3n86, 3n87, 3n8k, 3n8n

Cited: 22 times
EuropePMC logo PMID: 21410435

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.

Articles - 3n76 mentioned but not cited (4)

  1. Structure of type II dehydroquinase from Pseudomonas aeruginosa. Reiling S, Kelleher A, Matsumoto MM, Robinson G, Asojo OA. Acta Crystallogr F Struct Biol Commun 70 1485-1491 (2014)
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  3. Divide-and-conquer strategy for large-scale Eulerian solvent excluded surface. Zhao R, Wang M, Tong Y, Wei GW. Commun Inf Syst 18 299-329 (2018)
  4. FastGrow: on-the-fly growing and its application to DYRK1A. Penner P, Martiny V, Bellmann L, Flachsenberg F, Gastreich M, Theret I, Meyer C, Rarey M. J Comput Aided Mol Des 36 639-651 (2022)


Reviews citing this publication (3)

  1. Structural biology and drug discovery of difficult targets: the limits of ligandability. Surade S, Blundell TL. Chem Biol 19 42-50 (2012)
  2. The molecular biology of mycobacterial trehalose in the quest for advanced tuberculosis therapies. Nobre A, Alarico S, Maranha A, Mendes V, Empadinhas N. Microbiology (Reading) 160 1547-1570 (2014)
  3. Mycobacterium tuberculosis Shikimate Pathway Enzymes as Targets for the Rational Design of Anti-Tuberculosis Drugs. Nunes JES, Duque MA, de Freitas TF, Galina L, Timmers LFSM, Bizarro CV, Machado P, Basso LA, Ducati RG. Molecules 25 E1259 (2020)

Articles citing this publication (15)

  1. Structures of Helicobacter pylori shikimate kinase reveal a selective inhibitor-induced-fit mechanism. Cheng WC, Chen YF, Wang HJ, Hsu KC, Lin SC, Chen TJ, Yang JM, Wang WC. PLoS One 7 e33481 (2012)
  2. Elucidation of Mycobacterium tuberculosis type II dehydroquinase inhibitors using a fragment elaboration strategy. Tran AT, West NP, Britton WJ, Payne RJ. ChemMedChem 7 1031-1043 (2012)
  3. Structure-based virtual screening as a tool for the identification of novel inhibitors against Mycobacterium tuberculosis 3-dehydroquinate dehydratase. Petersen GO, Saxena S, Renuka J, Soni V, Yogeeswari P, Santos DS, Bizarro CV, Sriram D. J Mol Graph Model 60 124-131 (2015)
  4. Discovery of Schaeffer's acid analogues as lead structures of mycobacterium tuberculosis type II dehydroquinase using a rational drug design approach. Schmidt MF, Korb O, Howard NI, Dias MV, Blundell TL, Abell C. ChemMedChem 8 54-58 (2013)
  5. Synthesis of 3-alkyl enol mimics inhibitors of type II dehydroquinase: factors influencing their inhibition potency. Blanco B, Sedes A, Peón A, Lamb H, Hawkins AR, Castedo L, González-Bello C. Org Biomol Chem 10 3662-3676 (2012)
  6. Comparative binding energy COMBINE analysis for understanding the binding determinants of type II dehydroquinase inhibitors. Peón A, Coderch C, Gago F, González-Bello C. ChemMedChem 8 740-747 (2013)
  7. Mechanistic insight into the reaction catalysed by bacterial type II dehydroquinases. Coderch C, Lence E, Peón A, Lamb H, Hawkins AR, Gago F, González-Bello C. Biochem J 458 547-557 (2014)
  8. QM/MM simulations identify the determinants of catalytic activity differences between type II dehydroquinase enzymes. Lence E, van der Kamp MW, González-Bello C, Mulholland AJ. Org Biomol Chem 16 4443-4455 (2018)
  9. When inhibitors do not inhibit: critical evaluation of rational drug design targeting chorismate mutase from Mycobacterium tuberculosis. Munack S, Leroux V, Roderer K, Ökvist M, van Eerde A, Gundersen LL, Krengel U, Kast P. Chem Biodivers 9 2507-2527 (2012)
  10. Binding studies and structure determination of the recombinantly produced type-II 3-dehydroquinate dehydratase from Acinetobacter baumannii. Iqbal N, Kumar M, Sharma P, Yadav SP, Kaur P, Sharma S, Singh TP. Int J Biol Macromol 94 459-465 (2017)
  11. Design and structural analysis of aromatic inhibitors of type II dehydroquinase from Mycobacterium tuberculosis. Howard NI, Dias MV, Peyrot F, Chen L, Schmidt MF, Blundell TL, Abell C. ChemMedChem 10 116-133 (2015)
  12. Molecular modeling of a series of dehydroquinate dehydratase type II inhibitors of Mycobacterium tuberculosis and design of new binders. Miranda PHS, Lourenço EMG, Morais AMS, de Oliveira PIC, Silverio PSSN, Jordão AK, Barbosa EG. Mol Divers 25 1-12 (2021)
  13. Unraveling the kinetic diversity of microbial 3-dehydroquinate dehydratases of shikimate pathway. Liu C, Liu YM, Sun QL, Jiang CY, Liu SJ. AMB Express 5 7 (2015)
  14. Reducing the Flexibility of Type II Dehydroquinase for Inhibition: A Fragment-Based Approach and Molecular Dynamics Study. Peón A, Robles A, Blanco B, Convertino M, Thompson P, Hawkins AR, Caflisch A, González-Bello C. ChemMedChem 12 1512-1524 (2017)
  15. Structural and Biochemical Analysis of 3-Dehydroquinate Dehydratase from Corynebacterium glutamicum. Lee CH, Kim S, Seo H, Kim KJ. J Microbiol Biotechnol 33 1595-1605 (2023)


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