Structural Studies

To obtain structural information about the interaction mode of these inhibitors in the active site of the enzymes, we have solved serveral complexes of the enzymes and the inhibitors developed in the group in collaboration with Dr. Mark J. van Raaij from the National Centre of Biotechnology in Madrid. Some of these crystal structures are shown here.

 

Crystal Structures List:

(a) Type II Dehydroquinase from Mycobacterium tuberculosis (Mt-DHQ2)

 

  • 2Y71 - Mt-DHQ2 Complexed with an inhibitor
  • 2Y77 - Mt-DHQ2 with an inhibitor
  • 2Y76 - Mt-DHQ2 with an inhibitor
  • 4B6O - Mt-DHQ2 complexed with (2S)-2-(4-methoxy)benzyl-3-Dehydroquinic Acid
  • 4B6P -Mt-DHQ2 complexed with (2S)-2-perfluorobenzyl-3-Dehydroquinic Acid
  • 4B6Q -Mt-DHQ2 complexed with (2R)-2-((Benzo[b]thiophen-5-yl)methyl)-3-Dehydroquinic Acid
  • 2XB8 - Mt-DHQ2 complexed with (2R)-2-(4-methoxy)benzyl-3-Dehydroquinic Acid
  • 4CIV - Mt-DHQ2 complexed with (1R,4R,5R)-1,4,5-trihydroxy-3-hydroxymethylcyclohex-2-en-1-carboxylic acid
  • 4CIW - Mt-DHQ2 complexed with (1R,4R,5R)-1,4,5-trihydroxy-3-(2-hydroxy)ethylcyclohex-2-en-1-carboxylic acid
  • 4CIX - Mt-DHQ2 Complexed with (1R,4R,5R)-1,4,5-trihydroxy-3-[(1S)-1-hydroxy-2-phenylethyl]cyclohex-2-en-1-carboxylic acid
  • 4CIY - Mt-DHQ2 Complexed with (1R,4R,5R)-1,4,5-trihydroxy-3-[(1R)-1-hydroxy-2-phenylethyl]cyclohex-2-en-1-carboxylic acid
  1. 2XB8 - Mt-DHQ2 complexed with Inhibitor Compound (2R)-2-(4-Methoxybenzyl)-3-Dehydroquinic Acid.
  2. 2Y71 - Mt-DHQ2 complexed with (1R,4S,5R)-1,4,5-Trihydroxy-3-((5-methylbenzo[b]thiophen-2-yl)methoxy)cyclohex-2-enecarboxylate.
  3. 2Y76 - Mt-DHQ2 complexed with (1R,4S,5R)-3-(Benzo[b]thiophen-5-ylmethoxy)-2-(Benzo[b]thiophen-5-ylmethyl)-1,4,5-trihydroxycyclohex-2-enecarboxylate.
  4. 2Y77 - Mt-DHQ2 complexed  with (1R,4S,5R)- 3-(Benzo[b]thiophen-5-ylmethoxy)-1,4,5-trihydroxy-2-(thiophen-2-ylmethyl)cyclohex-2-enecarboxylate.  
  5. 4B60 - Mt-DHQ2 complexed  with (2S)-2-perfluorobenzyl-3-dehydroquinic acid. 
  6. 4B6P - Mt-DHQ2 complexed  with (2S)-2-(4-methoxy)benzyl-3-dehydroquinic acid.
  7. 4B6Q - Mt-DHQ2 complexed with (2R)-2-((Benzo[b]thiophen-5-yl)methyl)-3-dehydroquinic acid.
  8. 4CIV - Mt-DHQ2 complexed with (1R,4R,5R)-1,4,5-trihydroxy-3-hydroxymethylcyclohex-2-en-1-carboxylic acid.
  9. 4CIW - Mt-DHQ2 complexed with (1R,4R,5R)-1,4,5-trihydroxy-3-(2-hydroxy)ethylcyclohex-2-en-1-carboxylic acid.
  10. 4CIX - Mt-DHQ2 complexed with (1R,4R,5R)-1,4,5-trihydroxy-3-[(1S)-1-hydroxy-2-phenyl]cyclohex-2-en-1-carboxylic acid.
  11. 4CIY - Mt-DHQ2 complexed with (1R,4R,5R)-1,4,5-trihydroxy-3-[(1S)-1-hydroxy-2-phenyl]cyclohex-2-en-1-carboxylic acid.

 

(b) Type II Dehydroquinase from Helicobacter pylori (Hp-DHQ2)

  • PDB 2WKS, 2.95 A
  • PDB 2XD9, 1.95 A
  • PDB 2XDA, 1.85 A
  • PDB 4B6R, 2.00 A
  • PDB 4B6S, 1.90 A
  • PDB 2XB9, 2.75 A
  1. 2WKS - Hp-DHQ2 in complex with a new carbasugar-thiophene Inhibitor.
  2. 2XB9 - Hp-DHQ2 in complex with Inhibitor compound (2R)-2-(4-Methoxybenzyl)-3-Dehydroquinic Acid.
  3. 2XD9 - Hp-DHQ2 in complex with inhibitor compound (4R,6R,7S)-4,6,7-trihydroxy-2-((E)-prop-1-enyl)-4,5,6,7-Tetrahydrobenzo[b]thiophene-4-carboxylic Acid.
  4. 2XDA - Hp-DHQ in complex with an inhibitor compound (4R,6R,7S)-2-(2-cyclopropyl)ethyl-4,6,7-trihydroxy-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carboxylic acid.
  5. 4B6R - Hp-DHQ2 in complex with (2S)-2-perfluorobenzyl-3-Dehydroquinic Acid.
  6. 4B6S - Hp-DHQ2 in complex with (2S)-2-(4-methoxy)benzyl-3-Dehydroquinic Acid.

(c) Type I Dehydroquinase from Salmonella typhi (St-DHQ1)

  • PDB 4CNO, 1.50 A
  • PDB 4CLM, 1.40 A
  • PDB 4UIO, 1.35 A
  • PDB 6H5C, 1.14 A
  • PDB 6H5D, 1.25 A
  • PDB 6H5G, 1.04 A
  • PDB 6H5J, 1.40 A
  • PDB 6SFE, 1.08A
  • PDB 6SFG, 1.23 A
  1. 4CNO - St-DHQ1 in complex with (2R)-2-methyldehydroquinic acid.
  2. 4CLM - St-DHQ1 covalently modified by an epoxide.
  3. 4UIO - St-DHQ1 covalently modified by 2-hydroxylethyl ammonium derivative.
  4. 6H5C - St-DHQ1 covalently modified by an hydroxylammonium derivative.
  5. 6H5D - St-DHQ1 covalently modified by an hydroxylammonium derivative.
  6. 6H5G - St-DHQ1 covalently modified by an hydroxylammonium derivative.
  7. 6H5J - St-DHQ1 covalently modified by a ketone.
  8. 6SFE - St-DHQ1 covalently modified by an 2-hydroxylethyl ammonium derivative.
  9. 6SFG - St-DHQ1 covalently modified by an epoxide.
  10. to be disclosed - St-DHQ1 covalently modified by an amine.
  11. to be disclosed - St-DHQ1 in complex with an epoxide.

(d) Type I Dehydroquinase from Staphylococcus aureus (Sa-DHQ1)

PDB 6SFH, 1.73A
PDB 6SFH, 1.73 A
  1. 6SFH - Sa-DHQ1 covalently modified by a 2-hydroxylethyl ammonium derivative.
  2. to be disclosed - Sa-DHQ1 covalently modified by an amine.

(e) Shikimate kinase from Mycobacterium tuberculosis (Mt-SK)

  1. 4BQS - Structure of M. tuberculosis Shikimate Kinase Complexed with a rigid substrate analog and ADP.