Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

ATPases as drug targets: learning from their structure

Nature Reviews Drug Discovery volume 1, pages 665–673 (2002)Cite this article

Key Points

  • ATPases form a large family of enzymes that use the energy made available by the hydrolysis of ATP to drive energetically unfavourable processes.

  • These enzymes are involved in many diseases, and are therefore the targets of several drugs that are under development or already on the market. Most of these drugs inhibit their target ATPase without binding directly at the nucleotide-binding site.

  • Alternatively, the design of competitive ATP inhibitors could be envisaged as a new way of targeting ATPases.

  • The study of the structure of various ATPases shows that they contain different types of nucleotide-binding site and interact in a different manner with the nucleotide. Moreover, cavities that are not occupied by the nucleotide are present at the active site of many ATPases. This indicates that several ATPases contain at their nucleotide-binding site the structural features required for the design of competitive inhibitors of ATP.

  • The recent synthesis of low-molecular-mass compounds that compete with ATP and inhibit Hsp90 and DNA gyrase B shows that competitive inhibitors of ATP can be obtained.

  • Therefore, as is the case for another family of nucleotide-binding proteins, the protein kinases, competitive inhibitors of ATP could be used to inhibit ATPases. However, so far, such inhibitors have been obtained only for a subfamily of ATPases, and it remains to be seen whether this approach can be generalized for other ATPases.

Abstract

ATPases are involved in several cellular functions, and are at the origin of various human diseases. They are therefore attractive drug targets, and various ATPase inhibitors are already on the market. However, most of these drugs are active without binding directly to the nucleotide-binding site. An alternative strategy to inhibit ATPases is to design competitive ATP inhibitors. This approach, which has been used successfully to design protein-kinase inhibitors, depends on the structure of the nucleotide-binding site. This review describes the structural features of the nucleotide-binding site of various ATPases and analyses how this structural information can be exploited for drug discovery.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: ATPases hydrolyse ATP to drive energetically unfavourable processes.
Figure 2: Three families of ATPases.
Figure 3: Conformation of the bound nucleotide.
Figure 4: Interactions at the adenosine-binding pocket.
Figure 5: Structure of Hsp90 and DNA-gyrase-B inhibitors.

Similar content being viewed by others

References

  1. Csermely, P., Schnaider, T., Soti, C., Prohaszka, Z. & Nardai, G. The 90-kDa molecular chaperone family: structure, function and clinical applications. A comprehensive review. Pharmacol. Ther. 79, 129–168 (1998).

    CAS  PubMed  Google Scholar 

  2. Ranson, N. A., White, H. E. & Saibil, H. R. Chaperonins. Biochem. J. 333, 233–242 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Hirokawa, N., Noda, Y. & Okada, Y. Kinesin and dynein superfamily proteins in organelle transport and cell division. Curr. Opin. Cell Biol. 10, 60–73 (1998).

    CAS  PubMed  Google Scholar 

  4. Langer, T. AAA proteases: cellular machines for degrading membrane proteins. Trends Biochem. Sci. 25, 247–251 (2000).

    CAS  PubMed  Google Scholar 

  5. Lee, D. G. & Bell, S. P. ATPase switches controlling DNA replication initiation. Curr. Opin. Cell Biol. 12, 280–285 (2000).

    CAS  PubMed  Google Scholar 

  6. Yang, W. Structure and function of mismatch repair proteins. Mutat. Res. 460, 245–256 (2000).

    CAS  PubMed  Google Scholar 

  7. Caruthers, J. M. & McKay, D. B. Helicase structure and mechanism. Curr. Opin. Struct. Biol. 12, 123–133 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Nishi, T. & Forgac, M. The vacuolar (H+)-ATPases — nature's most versatile proton pumps. Nature Rev. Mol. Cell Biol. 3, 94–103 (2002).

    CAS  Google Scholar 

  9. Stewart, A. et al. Phase I trial of XR9576 in healthy volunteers demonstrates modulation of P-glycoprotein in CD56+ lymphocytes after oral and intravenous administration. Clin. Cancer Res. 6, 4186–4191 (2000).

    CAS  PubMed  Google Scholar 

  10. Wood, M. A., McMahon, S. B. & Cole, M. D. An ATPase/helicase complex is an essential cofactor for oncogenic transformation by c-myc. Mol. Cell 5, 321–330 (2000).

    CAS  PubMed  Google Scholar 

  11. Yeo, H. J., Savvides, S. N., Herr, A. B., Lanka, E. & Waksman, G. Crystal structure of the hexameric traffic ATPase of the Helicobacter pylori type IV secretion system. Mol. Cell 6, 1461–1472 (2000).

    CAS  PubMed  Google Scholar 

  12. Cohen, P. Protein kinases — the major drug targets of the twenty-first century? Nature Rev. Drug Discov. 1, 309–315 (2002).

    CAS  Google Scholar 

  13. Scapin, G. Structural biology in drug design: selective protein kinase inhibitors. Drug Discov. Today 7, 601–611 (2002).

    CAS  PubMed  Google Scholar 

  14. Al-Obeidi, F. A. & Lam, K. S. Development of inhibitors for tyrosine kinases. Oncogene 19, 5690–5701 (2000).

    CAS  PubMed  Google Scholar 

  15. Traxler, P. et al. Tyrosine kinase inhibitors: from rational design to clinical trials. Med. Res. Rev. 21, 499–512 (2001).

    CAS  PubMed  Google Scholar 

  16. Xu, H., Niedenzu, T. & Saenger, W. DNA helicase RepA: cooperative ATPase activity and binding of nucleotides. Biochemistry 39, 12225–12233 (2000).

    CAS  PubMed  Google Scholar 

  17. Traxler, P. & Furet, P. Strategies toward the design of novel and selective protein tyrosine kinase inhibitors. Pharmacol. Ther. 82, 195–206 (1999).

    CAS  PubMed  Google Scholar 

  18. Rossmann, M. G., Moras, D. & Olsen, K. W. Chemical and biological evolution of nucleotide-binding protein. Nature 250, 194–199 (1974).

    CAS  PubMed  Google Scholar 

  19. Walker, J. E., Saraste, M., Runswick, M. J. & Gay, N. J. Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J. 1, 945–951 (1982).A seminal article on the structural conservation among ATP-binding proteins.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Saraste, M., Sibbald, P. R. & Wittinghofer, A. The P-loop — a common motif in ATP- and GTP-binding proteins. Trends Biochem. Sci. 15, 430–434 (1990).

    PubMed  Google Scholar 

  21. Schulz, G. E. Binding of nucleotides by proteins. Curr. Biol. 2, 61–67 (1992).

    CAS  Google Scholar 

  22. Bossemeyer, D. The glycine-rich sequence of protein kinases: a multifunctional element. Trends Biochem. Sci. 19, 201–205 (1994).

    CAS  PubMed  Google Scholar 

  23. Vetter, I. R. & Wittinghofer, A. Nucleoside triphosphate-binding proteins: different scaffolds to achieve phosphoryl transfer. Quart. Rev. Biophys. 32, 1–56 (1999).An extensive review on the structure of ATP-binding proteins.

    CAS  Google Scholar 

  24. Mushegian, A. R., Bassett, D. E., Jr, Boguski, M. S., Bork, P. & Koonin, E. V. Positionally cloned human disease genes: patterns of evolutionary conservation and functional motifs. Proc. Natl Acad. Sci. USA 94, 5831–5836 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ban, C. & Yang, W. Crystal structure and ATPase activity of MutL: implications for DNA repair and mutagenesis. Cell 95, 541–552 (1998).

    CAS  PubMed  Google Scholar 

  26. Guarne, A., Junop, M. S. & Yang, W. Structure and function of the N-terminal 40 kDa fragment of human PMS2: a monomeric GHL ATPase. EMBO J. 20, 5521–5531 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Bork, P., Sander, C. & Valencia, A. An ATPase domain common to prokaryotic cell cycle proteins, sugar kinases, actin, and Hsp70 heat shock proteins. Proc. Natl Acad. Sci. USA 89, 7290–7294 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Flaherty, K. M., McKay, D. B., Kabsch, W. & Holmes, K. C. Similarity of the three-dimensional structures of actin and the ATPase fragment of a 70-kDa heat shock cognate protein. Proc. Natl Acad. Sci. USA 88, 5041–5045 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bochtler, M. et al. The structures of HsIU and the ATP-dependent protease HsIU-HsIV. Nature 403, 800–805 (2000).

    CAS  PubMed  Google Scholar 

  30. Trame, C. B. & McKay, D. B. Structure of Haemophilus influenzae HslU protein in crystals with one-dimensional disorder twinning. Acta Crystallogr. D 57, 1079–1090 (2001).

    CAS  PubMed  Google Scholar 

  31. Olson, W. K. & Sussman, J. L. How flexible is the furanose ring? 1. A comparison of experimental and theoretical studies. J. Am. Chem. Soc. 104, 270–278 (1982).

    CAS  Google Scholar 

  32. Moodie, S. L. & Thornton, J. M. A study into the effects of protein binding on nucleotide conformation. Nucleic Acids Res. 21, 1369–1380 (1993).An extensive analysis of the binding of ATP in ATP-binding proteins.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Fersht, A. Enzyme Structure and Mechanism 2nd edn (W. H. Freeman & Co., New York, 1985).

    Google Scholar 

  34. Moodie, S. L., Mitchell, J. B. & Thornton, J. M. Protein recognition of adenylate: an example of a fuzzy recognition template. J. Mol. Biol. 263, 486–500 (1996).

    CAS  PubMed  Google Scholar 

  35. Zhao, S., Morris, G. M., Olson, A. J. & Goodsell, D. S. Recognition templates for predicting adenylate-binding sites in proteins. J. Mol. Biol. 314, 1245–1255 (2001).

    CAS  PubMed  Google Scholar 

  36. Denessiouk, K. A. & Johnson, M. S. When fold is not important: a common structural framework for adenine and AMP binding in 12 unrelated protein families. Proteins 38, 310–326 (2000).

    CAS  PubMed  Google Scholar 

  37. Roe, S. M. et al. Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J. Med. Chem. 42, 260–266 (1999).A structural analysis of the inhibition of Hsp90 by two natural compounds.

    CAS  PubMed  Google Scholar 

  38. Blagosklonny, M. V. Hsp-90-associated oncoproteins: multiple targets of geldanamycin and its analogs. Leukemia 16, 455–462 (2002).

    CAS  PubMed  Google Scholar 

  39. Grenert, J. P. et al. The amino-terminal domain of heat shock protein 90 (Hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates Hsp90 conformation. J. Biol. Chem. 272, 23843–23850 (1997).

    CAS  PubMed  Google Scholar 

  40. Stebbins, C. E. et al. Crystal structure of an Hsp90–geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 89, 239–250 (1997).

    CAS  PubMed  Google Scholar 

  41. Prodromou, C. et al. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 90, 65–75 (1997).

    CAS  PubMed  Google Scholar 

  42. Neckers, L. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol. Med. 8, S55–S61 (2002).

    CAS  PubMed  Google Scholar 

  43. Piper, P. W. The Hsp90 chaperone as a promising drug target. Curr. Opin. Investig. Drugs 2, 1606–1610 (2001).

    CAS  PubMed  Google Scholar 

  44. Besant, P. G, Lasker, M. V., Bui, C. D. & Turck, C. W. Inhibition of branched-chain α-keto acid dehydrogenase kinase and Sln1 yeast histidine kinase by the antifungal antibiotic radicicol. Mol. Pharmacol. 62, 289–296 (2002).

    CAS  PubMed  Google Scholar 

  45. Felts, S. J. et al. The Hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. J. Biol. Chem. 275, 3305–3312 (2000).

    CAS  PubMed  Google Scholar 

  46. Lucas, B., Rosen, N. & Chiosis, G. Facile synthesis of a library of 9-alkyl-8-benzyl-9H-purin-6-ylamine derivatives. J. Comb. Chem. 3, 518–520 (2001).

    CAS  PubMed  Google Scholar 

  47. Chiosis, G. et al. A small molecule designed to bind to the adenine nucleotide pocket of Hsp90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells. Chem. Biol. 8, 289–299 (2001).

    CAS  PubMed  Google Scholar 

  48. Gormley, N. A., Orphanides, G., Meyer, A., Cullis, P. M. & Maxwell, A. The interaction of coumarin antibiotics with fragments of DNA gyrase B protein. Biochemistry 35, 5083–5092 (1996).

    CAS  PubMed  Google Scholar 

  49. Lewis, R. J. et al. The nature of inhibition of DNA gyrase by the coumarins and the cyclothialidines revealed by X-ray crystallography. EMBO J. 15, 1412–1420 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Kim, O. K., Ohemeng, K. & Barrett, J. F. Advances in DNA gyrase inhibitors. Expert Opin. Investig. Drugs 10, 199–212 (2001).

    CAS  PubMed  Google Scholar 

  51. Oram, M. et al. Mode of action of GR122222X, a novel inhibitor of bacterial DNA gyrase. Antimicrob. Agents Chemother. 40, 473–476 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Boehm, H. J. et al. Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening. J. Med. Chem. 43, 2664–2674 (2000).An example of the synthesis of a competitive inhibitor of ATP (DNA gyrase).

    CAS  PubMed  Google Scholar 

  53. Hopkins, S. C., Vale, R. D. & Kuntz, I. D. Inhibitors of kinesin activity from structure-based computer screening. Biochemistry 39, 2805–2814 (2000).

    CAS  PubMed  Google Scholar 

  54. Davies, S. P., Reddy, H., Caivano, M. & Cohen, P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351, 95–105 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Mayer, T. U. et al. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286, 971–974 (1999).

    CAS  PubMed  Google Scholar 

  56. Cheung, A. et al. A small-molecule inhibitor of skeletal muscle myosin II. Nature Cell Biol. 4, 83–88 (2002).

    CAS  PubMed  Google Scholar 

  57. Eichhorn, E. J. & Gheorghiade, M. Digoxin. Prog. Cardiovasc. Dis. 44, 251–266 (2002).

    CAS  PubMed  Google Scholar 

  58. Martin, C. et al. The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein. Br. J. Pharmacol. 128, 403–411 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Horn, J. The proton-pump inhibitors: similarities and differences. Clin. Ther. 22, 266–280 (2000).

    CAS  PubMed  Google Scholar 

  60. Gagliardi, S., Rees, M. & Farina, C. Chemistry and structure activity relationships of bafilomycin A1, a potent and selective inhibitor of the vacuolar H+-ATPase. Curr. Med. Chem. 6, 1197–1212 (1999).

    CAS  PubMed  Google Scholar 

  61. Hu, T., Sage, H. & Hsieh, T. S. ATPase domain of eukaryotic DNA topoisomerase II. Inhibition of ATPase activity by the anti-cancer drug bisdioxopiperazine and ATP/ADP-induced dimerization. J. Biol. Chem. 277, 5944–5951 (2002).

    CAS  PubMed  Google Scholar 

  62. Gulick, A. M., Bauer, C. B., Thoden, J. B. & Rayment, I. X-ray structures of the MgADP, MgATPγS, and MgAMPPNP complexes of the Dictyostelium discoideum myosin motor domain. Biochemistry 36, 11619–11628 (1997).

    CAS  PubMed  Google Scholar 

  63. Turner, J. et al. Crystal structure of the mitotic spindle kinesin Eg5 reveals a novel conformation of the neck-linker. J. Biol. Chem. 276, 25496–25502 (2001).

    CAS  PubMed  Google Scholar 

  64. Kikkawa, M. et al. Switch-based mechanism of kinesin motors. Nature 411, 439–445 (2001).

    CAS  PubMed  Google Scholar 

  65. Song, Y. H. et al. Structure of a fast kinesin: implications for ATPase mechanism and interactions with microtubules. EMBO J. 20, 6213–6225 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kull, F. J., Sablin, E. P., Lau, R., Fletterick, R. J. & Vale, R. D. Crystal structure of the kinesin motor domain reveals a structural similarity to myosin. Nature 380, 550–555 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Sablin, E. P. et al. Direction determination in the minus-end-directed kinesin motor Ncd. Nature 395, 813–816 (1998).

    CAS  PubMed  Google Scholar 

  68. Yun, M., Zhang, X., Park, C. G., Park, H. W. & Endow, S. A. A structural pathway for activation of the kinesin motor ATPase. EMBO J. 20, 2611–2618 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Hopfner, K. P. et al. Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily. Cell 101, 789–800 (2000).

    CAS  PubMed  Google Scholar 

  70. Lamers, M. H. et al. The crystal structure of DNA mismatch repair protein MutS binding to a G × T mismatch. Nature 407, 711–717 (2000).

    CAS  PubMed  Google Scholar 

  71. Yuan, Y. R. et al. The crystal structure of the MJ0796 ATP-binding cassette. Implications for the structural consequences of ATP hydrolysis in the active site of an ABC transporter. J. Biol. Chem. 276, 32313–32321 (2001).

    CAS  PubMed  Google Scholar 

  72. Karpowich, N. et al. Crystal structures of the MJ1267 ATP binding cassette reveal an induced-fit effect at the ATPase active site of an ABC transporter. Structure 9, 571–586 (2001).

    CAS  PubMed  Google Scholar 

  73. Gaudet, R. & Wiley, D. C. Structure of the ABC ATPase domain of human TAP1, the transporter associated with antigen processing. EMBO J. 20, 4964–4972 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Soultanas, P., Dillingham, M. S., Velankar, S. S. & Wigley, D. B. DNA binding mediates conformational changes and metal ion coordination in the active site of PcrA helicase. J. Mol. Biol. 290, 137–148 (1999).

    CAS  PubMed  Google Scholar 

  75. Putnam, C. D. et al. Structure and mechanism of the RuvB Holliday junction branch migration motor. J. Mol. Biol. 311, 297–310 (2001).

    CAS  PubMed  Google Scholar 

  76. Oyama, T., Ishino, Y., Cann, I. K., Ishino, S. & Morikawa, K. Atomic structure of the clamp loader small subunit from Pyrococcus furiosus. Mol. Cell 8, 455–463 (2001).

    CAS  PubMed  Google Scholar 

  77. Lenzen, C. U., Steinmann, D., Whiteheart, S. W. & Weis, W. I. Crystal structure of the hexamerization domain of N-ethylmaleimide-sensitive fusion protein. Cell 94, 525–536 (1998).

    CAS  PubMed  Google Scholar 

  78. Zhang, X. et al. Structure of the AAA ATPase p97. Mol. Cell 6, 1473–1484 (2000).

    CAS  PubMed  Google Scholar 

  79. Liu, J. et al. Structure and function of Cdc6/Cdc18: implications for origin recognition and checkpoint control. Mol. Cell 6, 637–648 (2000).

    CAS  PubMed  Google Scholar 

  80. Singleton, M. R., Sawaya, M. R., Ellenberger, T. & Wigley, D. B. Crystal structure of T7 gene 4 ring helicase indicates a mechanism for sequential hydrolysis of nucleotides. Cell 101, 589–600 (2000).

    CAS  PubMed  Google Scholar 

  81. Menz, R. I., Walker, J. E. & Leslie, A. G. Structure of bovine mitochondrial F(1)-ATPase with nucleotide bound to all three catalytic sites: implications for the mechanism of rotary catalysis. Cell 106, 331–341 (2001).

    CAS  PubMed  Google Scholar 

  82. Hayashi, I., Oyama, T. & Morikawa, K. Structural and functional studies of MinD ATPase: implications for the molecular recognition of the bacterial cell division apparatus. EMBO J. 20, 1819–1828 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhou, T., Radaev, S., Rosen, B. P. & Gatti, D. L. Conformational changes in four regions of the Escherichia coli ArsA ATPase link ATP hydrolysis to ion translocation. J. Biol. Chem. 276, 30414–30422 (2001).

    CAS  PubMed  Google Scholar 

  84. Schutt, C. E., Myslik, J. C., Rozycki, M. D., Goonesekere, N. C. & Lindberg, U. The structure of crystalline profilin–β-actin. Nature 365, 810–816 (1993).

    CAS  PubMed  Google Scholar 

  85. Van den Ent, F. & Lowe, J. Crystal structure of the cell division protein FtsA from Thermotoga maritima. EMBO J. 19, 5300–5307 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Osipiuk, J., Walsh, M. A., Freeman, B. C., Morimoto, R. I. & Joachimiak, A. Structure of a new crystal form of human Hsp70 ATPase domain. Acta Crystallogr. D 55, 1105–1107 (1999).

    CAS  PubMed  Google Scholar 

  87. Obermann, W. M., Sondermann, H., Russo, A. A., Pavletich, N. P. & Hartl, F. U. In vivo function of Hsp90 is dependent on ATP binding and ATP hydrolysis. J. Cell Biol. 143, 901–910 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Brino, L. et al. Dimerization of Escherichia coli DNA-gyrase B provides a structural mechanism for activating the ATPase catalytic center. J. Biol. Chem. 275, 9468–9475 (2000).

    CAS  PubMed  Google Scholar 

  89. Ban, C., Junop, M. & Yang, W. Transformation of MutL by ATP binding and hydrolysis: a switch in DNA mismatch repair. Cell 97, 85–97 (1999).

    CAS  PubMed  Google Scholar 

  90. Berman, H. M. et al. The Protein Data Bank. Nucleic Acids Res. 28, 235–242 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Oncology Department, Novartis, K125 442, Basel, CH-4002, Switzerland

    Patrick Chène

Authors
  1. Patrick Chène
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

Cancer.gov

breast cancer

LocusLink

ABL

BCR

c-MYC

DNA topoisomerase II

ERBB2

H+,K+ pump

kinesins

KIF1A

Na+,K+-ATPase

P-glycoprotein

TIP49

TRAP1

vacuolar H+-ATPase

v-SRC

Medscape DrugInfo

Cipro

Gleevec

Prilosec

Protein Data Bank

ArsA

β-actin

Cdc6

DNA gyrase B

Eg5

F1-ATPase

FtsA

HP0525

HslU

Hsp70

Hsp90

Kar3

KIF1A

KIF5B

MinD

MJ0796

MJ1267

MutL

MutS

myosin

Ncd

NcKin

NSF

p97

PcrA

PMS2

Rad50

RFCS

RuvB

T7 gene 4 ring helicase

TAP1

<i>Saccharomyces</i> Genome Database

Sln1

FURTHER INFORMATION

Swiss-PDB Viewer

Glossary

AAA-ATPase FAMILY

The AAA (for ATPases associated with various cellular activities) ATPase superfamily is characterized by a highly conserved module of ∼230 amino-acid residues, including one or two copies of an ATP-binding consensus sequence.

BIOAVAILABILITY

The amount of a drug that is absorbed into the body.

HYDROGEN BOND

(H-bond). A weak electrostatic link between an electronegative atom, such as oxygen, and a hydrogen atom that is linked covalently to another electronegative atom, such as nitrogen.

HYDROPHOBIC

Hydrophobic regions of proteins are formed by nonpolar amino acids. They are usually located in the interior of proteins.

DIPOLE MOMENT

An electric dipole is constituted by two distant electric charges of opposite sign. The dipole moment is defined as the product of the total amount of positive or negative charge and the distance between them.

GHL ATPase FAMILY

The name of a subfamily of ATPases that have the same type of nucleotide-binding site as the one found in DNA gyrase B, Hsp90 and MutL proteins.

EXOCYCLIC

A chemical substitution on a cyclic molecule.

PUCKERS

The term pucker reflects that the five atoms that constitute the five-membered ring of the sugar are not in the same plane.

SOLVATION SHELL

The layer of water molecules that surrounds a solute in a solvent.

ENTHALPIC

In a chemical reaction, the enthalpy represents approximately the difference between the energy that needs to be put in to break the chemical bonds, and the energy gained from new chemical-bond formation.

ENTROPIC

The entropy measures the amount of disorder in a system.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chène, P. ATPases as drug targets: learning from their structure. Nat Rev Drug Discov 1, 665–673 (2002). https://doi.org/10.1038/nrd894

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd894

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing