[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

A molecular mechanism of P-loop pliability of Rho-kinase investigated by molecular dynamic simulation

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

Rho-kinase is a leading player in the regulation of cytoskeletal events involving smooth muscle contraction and neurite growth-cone collapse and retraction, and is a promising drug target in the treatment of both vascular and neurological disorders. Recent crystal structure of Rho-kinase complexed with a small-molecule inhibitor fasudil has revealed structural details of the ATP-binding site, which represents the target site for the inhibitor, and showed that the conserved phenylalanine on the P-loop occupies the pocket, resulting in an increase of protein–ligand contacts. Thus, the P-loop pliability is considered to play an important role in inhibitor binding affinity and specificity. In this study, we carried out a molecular dynamic simulation for Rho-kinase–fasudil complexes with two different P-loop conformations, i.e., the extended and folded conformations, in order to understand the P-loop pliability and dynamics at atomic level. A PKA–fasudil complex was also used for comparison. In the MD simulation, the flip-flop movement of the P-loop conformation starting either from the extended or folded conformation was not able to be observed. However, a significant conformational change in a long loop region covering over the P-loop, and also alteration of ionic interaction-manner of fasudil with acidic residues in the ATP binding site were shown only in the Rho-kinase–fasudil complex with the extended P-loop conformation, while Rho-kinase with the folded P-loop conformation and PKA complexes did not show large fluctuations, suggesting that the Rho-kinase–fasudil complex with the extended P-loop conformation represents a meta-stable state. The information of the P-loop pliability at atomic level obtained in this study could provide valuable clues to designing potent and/or selective inhibitors for Rho-kinase.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14

Similar content being viewed by others

References

  1. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K (1996) Science 273:245

    Article  CAS  Google Scholar 

  2. Matsui T, Amano M, Yamamoto T, Chihara K, Nakafuku M, Ito M, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K (1996) EMBO J 15:2208

    CAS  Google Scholar 

  3. Leung T, Manser E, Tan L, Lim L (1995) J Biol Chem 270:29051

    Article  CAS  Google Scholar 

  4. Leung T, Chen XQ, Manser E, Lim L (1996) Mol Cell Biol 16:5313

    CAS  Google Scholar 

  5. Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A, Watanabe N, Saito Y, Kakizuka A, Morii N, Narumiya S (1996) EMBO J 15:1885

    CAS  Google Scholar 

  6. Amano M, Chihara K, Nakamura N, Kaneko T, Matsuura Y, Kaibuchi K (1999) J Biol Chem 274:32418

    Article  CAS  Google Scholar 

  7. Chen XQ, Tan I, Ng CH, Hall C, Lim L, Leung T (2002) J Biol Chem 277:12680

    Article  CAS  Google Scholar 

  8. Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K (1996) J Biol Chem 271:20246

    Article  CAS  Google Scholar 

  9. Kaibuchi K, Kuroda S, Amano M (1999) Annu Rev Biochem 68:459

    Article  CAS  Google Scholar 

  10. Riento K, Ridley A (2003) Nat Rev Mol Cell Biol 4:446

    Article  CAS  Google Scholar 

  11. Mueller BK, Mack H, Teusch N (2005) Nat Rev Drug Discov 4:387

    Article  CAS  Google Scholar 

  12. Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Midori Maekawa M, Narumiya S (1997) Nature 389:990

    Article  CAS  Google Scholar 

  13. Ono-Saito N, Niki I, Hidaka H (1999) Pharmacol Ther 82:123

    Article  CAS  Google Scholar 

  14. Yamaguchi H, Kasa M, Amano M, Kaibuchi K, Hakoshima T (2006) Structure 14:589

    Article  CAS  Google Scholar 

  15. Noble ME, Endicott JA, Johnson LN (2004) Science 303:1800

    Article  CAS  Google Scholar 

  16. Breitenlechner C, Gassel M, Hidaka H, Kinzel V, Huber R, Engh RA, Bossemeyer D (2003) Structure 11:1595

    Article  CAS  Google Scholar 

  17. Case DA, Darden TA, Cheatham TE III, Simmerling CL, Wang J, Duke RE, Luo R, Merz KM, Pearlman DA, Crowley M, Walker RC, Zhang W, Wang B, Hayik S, Roitberg A, Seabra G, Wong KF, Paesani F, Wu X, Brozell S, Tsui V, Gohlke H, Yang L, Tan C, Mongan J, Hornak V, Cui G, Beroza P, Mathews DH, Schafmeister C, Ross WS, Kollman PA (2006) Manual of AMBER 9. University of California, San Francisco

    Google Scholar 

  18. Yang L, Tan CH, Hsieh MJ, Wang J, Duan Y, Cieplak P, Caldwell J, Kollman PA, Luo R (2006) J Phys Chem B 110:13166

    Article  CAS  Google Scholar 

  19. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) J Comput Chem 25:1157

    Article  CAS  Google Scholar 

  20. Bonn S, Herrero S, Breitenlechner CB, Erlbruch A, Lehmann W, Engh RA, Gassel M, Bossemeyer D (2006) J Biol Chem 281:24818

    Article  CAS  Google Scholar 

  21. Bártová I, Otyepka M, Kríz Z, Koca J (2004) Protein Sci 13:1449

    Article  Google Scholar 

  22. Bártová I, Otyepka M, Kríz Z, Koca J (2005) Protein Sci 14:445

    Article  Google Scholar 

  23. Bártová I, Koca J, Otyepka M (2008) Protein Sci 17:22

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Computer-Aided Molecular Modeling Research Center Kansai, 1-3-12 Honjyo-cho, Higashinada-ku, Kobe, Hyogo, 658-0012, Japan

    Keigo Gohda

  2. Nara Institute of Science and Technology, 8916-5, Takayama, Ikoma, Nara, 630-0192, Japan

    Toshio Hakoshima

Authors
  1. Keigo Gohda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshio Hakoshima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshio Hakoshima.

Electronic supplementary material

Below are the electronic supplementary materials.

(DOC 27 kb)

(DOC 28 kb)

(DOC 24 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gohda, K., Hakoshima, T. A molecular mechanism of P-loop pliability of Rho-kinase investigated by molecular dynamic simulation. J Comput Aided Mol Des 22, 789–797 (2008). https://doi.org/10.1007/s10822-008-9214-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-008-9214-7

Keywords

Search

Navigation