Refined solution structure of the LpxC-TU-514 complex and pKa analysis of an active site histidine: Insights into the mechanism and inhibitor design

Biochemistry

Volumn 44, Issue 4, 2005, Pages 1114-1126

  Coggins, Brian E ^a   McClerren, Amanda L ^a   Jiang, Ling ^a   Li, Xuechen ^b,c   Rudolph, Johannes ^a   Hindsgaul, Ole ^b,d   Raetz, Christian R H ^a   Zhou, Pei ^a  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

^b UNIVERSITY OF ALBERTA   (Canada)

^c HARVARD UNIVERSITY   (United States)

^d CARLSBERG LABORATORY   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

BIOCHEMISTRY; CATALYSIS; CELLS; ENZYME INHIBITION; ENZYMES; LIPIDS; NUCLEAR MAGNETIC RESONANCE; PH EFFECTS; POLYSACCHARIDES; X RAY ANALYSIS;

AQUIFEX AEOLICUS; DIPOLAR COUPLING; HISTIDINES; METALLOAMIDASES;

BACTERIA;

1,5 ANHYDRO 2 C (CARBOXYMETHYL N HYDROXYAMIDE) 2 DEOXY 3 O MYRISTOYLGLUCITOL; AMIDASE; CARBON 13; LIPID A; LIPOPOLYSACCHARIDE; SORBITOL; TU 514; UNCLASSIFIED DRUG; URIDINE DIPHOSPHATE 3 O ACYL N ACETYLGLUCOSAMINE DEACETYLASE;

ANTIBACTERIAL ACTIVITY; ARTICLE; BIOCHEMISTRY; CATALYSIS; CELL VIABILITY; CHEMICAL STRUCTURE; ENZYME ACTIVE SITE; ENZYME INHIBITION; ENZYME MECHANISM; NUCLEAR MAGNETIC RESONANCE; PRIORITY JOURNAL; PROTEIN FAMILY; PROTEIN STRUCTURE; SEQUENCE HOMOLOGY; X RAY ANALYSIS;

AMIDOHYDROLASES; AQUIFOLIACEAE; BINDING SITES; CATALYSIS; CONSERVED SEQUENCE; CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; GLYCOLIPIDS; HEXOSES; HISTIDINE; HYDROGEN-ION CONCENTRATION; MUTAGENESIS, SITE-DIRECTED; NUCLEAR MAGNETIC RESONANCE, BIOMOLECULAR; PROTONS; SOLUTIONS; SUBSTRATE SPECIFICITY; THERMODYNAMICS;

AQUIFEX AEOLICUS; MAMMALIA; NEGIBACTERIA;

EID: 13444287735     PISSN: 00062960     EISSN: None     Source Type: Journal    
DOI: 10.1021/bi047820z     Document Type: Article

References (52)

1. Raetz, C. R. H., and Whitfield, C. (2002) Lipopolysaccharide endotoxins, Annu. Rev. Biochem. 71, 635-700.
2. Jackman, J. E., Raetz, C. R. H., and Fierke, C. A. (1999) UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase of Escherichia coli is a zinc metalloenzyme, Biochemistry 38, 1902-1911.
3. Coggins, B. E., Li, X., McClerren, A. L., Hindsgaul, O., Raetz, C. R. H., and Zhou, P. (2003) Structure of the LpxC deacetylase with a bound substrate-analog inhibitor, Nat. Struct. Biol. 10, 645-651.
4. Whittington, D. A., Rusche, K. M., Shin, H., Fierke, C. A., and Christianson, D. W. (2003) Crystal structure of LpxC, a zinc-dependent deacetylase essential for endotoxin biosynthesis, Proc. Natl. Acad. Sci. U.S.A. 100, 8146-8150.
5. Jackman, J. E., Raetz, C. R. H., and Fierke, C. A. (2001) Site-directed mutagenesis of the bacterial metalloamidase UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC). Identification of the zinc binding site, Biochemistry 40, 514-523.
6. Onishi, H. R., Pelak, B. A., Gerckens, L. S., Silver, L. L., Kahan, F. M., Chen, M. H., Patchett, A. A., Galloway, S. M., Hyland, S. A., Anderson, M. S., and Raetz, C. R. H. (1996) Antibacterial agents that inhibit lipid A biosynthesis, Science 274, 980-982.
7. Jackman, J. E., Fierke, C. A., Tumey, L. N., Pirrung, M., Uchiyama, T., Tahir, S. H., Hindsgaul, O., and Raetz, C. R. H. (2000) Antibacterial agents that target lipid A biosynthesis in gram-negative bacteria. Inhibition of diverse UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylases by substrate analogs containing zinc binding motifs, J. Biol. Chem. 275, 11002-11009.
8. Clore, G. M., and Gronenborn, A. M. (1998) New methods of structure refinement for macromolecular structure determination by NMR, Proc. Natl. Acad. Sci. U.S.A. 95, 5891-5898.
9. Bax, A. (2003) Weak alignment offers new NMR opportunities to study protein structure and dynamics, Protein Sci. 12, 1-16.
10. Lipsitz, R. S., and Tjandra, N. (2004) Residual dipolar couplings in NMR structure analysis, Annu. Rev. Biophys. Biomol. Struct. 33, 387-413.
11. Prestegard, J. H., Bougault, C. M., and Kishore, A. I. (2004) Residual dipolar couplings in structure determination of biomolecules, Chem. Rev. 104, 3519-3540.
12. Whistler, R. L., Wolfrom, M. L., BeMiller, J. N., and Shafizadeh, F. (1963) Methods in Carbohydrate Chemistry, pp 409-410, Academic Press, New York.
13. Li, X., Uchiyama, T., Raetz, C. R. H., and Hindsgaul, O. (2003) Synthesis of a carbohydrate-derived hydroxamic acid inhibitor of the bacterial enzyme (LpxC) involved in lipid A biosynthesis, Org. Lett. 5, 539-541.
14. 2H-labeled proteins, J. Biomol. NMR 14, 333-343.
15. Ottiger, M., Delaglio, F., and Bax, A. (1998) Measurement of J and dipolar couplings from simplified two-dimensional NMR spectra, J. Magn. Reson. 131, 373-378.
16. Delaglio, F., Grzesiek, S., Vuister, G. W., Zhu, G., Pfeifer, J., and Bax, A. (1995) NMRPipe: a multidimensional spectral processing system based on UNIX pipes, J. Biomol. NMR 6, 277-293.
17. Bartels, C., Xia, T., Billeter, M., Güntert, P., and Wüthrich, K. (1995) The program XEASY for computer-supported NMR spectral analysis of biological macromolecules, J. Biol. NMR 6, 1-10.
18. Garrett, D. S., Powers, R., Gronenborn, A. M., and Clore, G. M. (1991) A common sense approach to peak picking in two-, three-, and four-domensional spectra using automatic computer analysis of contour diagrams, J. Magn. Reson. 95, 214-220.
19. Clore, G. M., Gronenborn, A. M., and Bax, A. (1998) A robust method for determining the magnitude of the fully asymmetric alignment tensor of oriented macromolecules in the absence of structural information, J. Magn. Reson. 133, 216-221.
20. Dosset, P., Hus, J. C., Marion, D., and Blackledge, M. (2001) A novel interactive tool for rigid-body modeling of multi-domain macromolecules using residual dipolar couplings, J. Biomol. NMR 20, 223-231.
21. Schwieters, C. D., Kuszewski, J. J., Tjandra, N., and Clore, G. M. (2003) The Xplor-NIH NMR molecular structure determination package, J. Magn. Reson. 160, 65-73.
22. Okar, D. A., Felicia, N. D., Gui, L., and Lange, A. J. (1997) Labeling of recombinant protein for NMR spectroscopy: global and specific labeling of the rat liver fructose 2,6-bisphosphatase domain, Protein Expression Purif. 11, 79-85.
23. Markley, J. L., Bax, A., Arata, Y., Hilbers, C. W., Kaptein, R., Sykes, B. D., Wright, P. E., and Wüthrich, K. (1998) Recommendations for the presentation of NMR structures of proteins and nucleic acids, Pure Appl. Chem. 70, 117-142.
24. McClerren, A. L., Zhou, P., Guan, Z., Raetz, C. R. H., and Rudolph, J. (2004) Kinetic analysis of the zinc-dependent deacetylase in the lipid A biosynthetic pathway, Biochemistry 43, 1106-1113.
25. Fersht, A. (1999) Structure and Mechanism in Protein Science: A Guide to Enzyme Catalysis and Protein Folding, W. H. Freeman and Co., New York.
26. Cleland, W. W. (1979) Statistical analysis of enzyme kinetic data, Methods Enzymol. 63, 103-138.
27. Breeze, A. L. (2000) Isotope-filtered NMR methods for the study of biomolecular structure and interactions, Prog. Nucl. Magn. Reson. Spectrosc. 36, 323-372.
28. Walters, K. J., Ferentz, A. E., Hare, B. J., Hidalgo, P., Jasanoff, A., Matsuo, H., and Wagner, G. (2001) Characterizing protein-protein complexes and oligomers by nuclear magnetic resonance spectroscopy, Methods Enzymol. 339, 238-258.
29. Zwahlen, C., Legault, P., Vincent, S. J. F., Greenblatt, J., Konrat, R., and Kay, L. E. (1997) Methods for Measurement of Intermolecular NOEs by Multinuclear NMR Spectroscopy: Application to a Bacteriophage N-Peptide/boxB RNA Complex, J. Am. Chem. Soc. 119, 6711-6721.
30. Walters, K. J., Matsuo, H., and Wagner, G. (1997) A Simple Method to Distinguish Intermonomer Nuclear Overhauser Effects in Homodimeric Proteins with C2 Symmetry, J. Am. Chem. Soc. 119, 5958-5959.
31. Walters, K. J., Dayie, K. T., Reece, R. J., Ptashne, M., and Wagner, G. (1997) Structure and mobility of the PUT3 dimer, Nat. Struct. Biol. 4, 744-750.
32. Zhou, P., Sun, L. J., Dötsch, V., Wagner, G., and Verdine, G. L. (1998) Solution structure of the core NFATC1/DNA complex, Cell 92, 687-696.
33. Ferentz, A. E., Opperman, T., Walker, G. C., and Wagner, G. (1997) Dimerization of the UmuD′ protein in solution and its implications for regulation of SOS mutagenesis, Nat. Struct. Biol. 4, 979-983.
34. Woolley, P. (1975) Models for metal ion function in carbonic anhydrase, Nature 258, 677-682.
35. Kunugi, S., Hirohara, H., and Ise, N. (1982) pH and temperature dependences of thermolysin catalysis. Catalytic role of zinc-coordinated water, Eur. J. Biochem. 124, 157-163.
36. Izatt, R. M., and Christensen, J. J. (1976) Heats of proton ionization, pK, and related thermodynamic quantities, 3rd ed., Vol. 1, CRC Press, Cleveland, OH.
37. Christianson, D. W., and Lipscomb, W. N. (1989) Carboxypeptidase A, Acc. Chem. Res. 22, 62-69.
38. Matthews, B. W. (1988) Structural basis of the action of thermolysin and related zinc peptidases, Acc. Chem. Res. 21, 333-340.
39. Beaumont, A., O'Donohue, M. J., Paredes, N., Rousselet, N., Assicot, M., Bohuon, C., Fournie-Zaluski, M. C., and Roques, B. P. (1995) The role of histidine 231 in thermolysin-like enzymes. A site-directed mutagenesis study, J. Biol. Chem. 270, 16803-16808.
40. Phillips, M. A., Fletterick, R., and Rutter, W. J. (1990) Arginine 127 stabilizes the transition state in carboxypeptidase, J. Biol. Chem. 265, 20692-20698.
41. Harris, T. K., and Turner, G. J. (2002) Structural basis of perturbed pKa values of catalytic groups in enzyme active sites, IUBMB Life 53, 85-98.
42. Pirrung, M. C., Tumey, L. N., McClerren, A. L., and Raetz, C. R. H. (2003) High-throughput catch-and-release synthesis of oxazoline hydroxamates. Structure-activity relationships in novel inhibitors of Escherichia coli LpxC: in vitro enzyme inhibition and antibacterial properties, J. Am. Chem. Soc. 125, 1575-1586.
43. Pirrung, M. C., Tumey, L. N., Raetz, C. R. H., Jackman, J. E., Snehalatha, K., McClerren, A. L., Fierke, C. A., Gantt, S. L., and Rusche, K. M. (2002) Inhibition of the antibacterial target UDP-(3-O-acyl)-N- acetylglucosamine deacetylase (LpxC): isoxazoline zinc amidase inhibitors bearing diverse metal binding groups, J. Med. Chem. 45, 4359-4370.
44. Kline, T., Andersen, N. H., Harwood, E. A., Bowman, J., Malanda, A., Endsley, S., Erwin, A. L., Doyle, M., Fong, S., Harris, A. L., Mendelsohn, B., Mdluli, K., Raetz, C. R. H., Stover, C. K., Witte, P. R., Yabannavar, A., and Zhu, S. (2002) Potent, novel in vitro inhibitors of the Pseudomonas aeruginosa deacetylase LpxC, J. Med. Chem. 45, 3112-3129.
45. Clements, J. M., Coignard, F., Johnson, I., Chandler, S., Palan, S., Waller, A., Wijkmans, J., and Hunter, M. G. (2002) Antibacterial Activities and Characterization of Novel Inhibitors of LpxC, Antimicrob. Agents Chemother. 46, 1793-1799.
46. Cornilescu, G., Delaglio, F., and Bax, A. (1999) Protein backbone angle restraints from searching a database for chemical shift and sequence homology, J. Biomol. NMR 13, 289-302.
47. Güntert, P., Mumenthaler, C., and Wüthrich, K. (1997) Torsion angle dynamics for NMR structure calculation with the new program DYANA, J. Mol. Biol. 273, 283-298.
48. Clore, G. M., and Garrett, D. S. (1999) R-factor, Free R, and complete cross-validation for dipolar coupling refinement of NMR structures, J. Am. Chem. Soc. 121, 9008-9012.
49. Davis, I. W., Murray, L. W., Richardson, J. S., and Richardson, D. C. (2004) MOLPROBITY: structure validation and all-atom contact analysis for nucleic acids and their complexes, Nucleic Acids Res. 32, W615-W619.
50. Lovell, S. C., Davis, I. W., Arendall, W. B., 3rd, de Bakker, P. I., Word, J. M., Prisant, M. G., Richardson, J. S., and Richardson, D. C. (2003) Structure validation by Cα geometry: φ,ψ and Cβ deviation, Proteins 50, 437-450.
51. Petrey, D., and Honig, B. (2003) GRASP2: visualization, surface properties, and electrostatics of macromolecular structures and sequences, Methods Enzymol. 374, 492-509.
52. Koradi, R., Billeter, M., and Wüthrich, K. (1996) MOLMOL: a program for display and analysis of macromolecular structures, J. Mol. Graphics 14, 51-55.