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Volume 11 Supplement 1

5th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

Structural insights into sGC activation by different activators

BMC Pharmacology volume 11, Article number: O11 (2011) Cite this article

Background

The soluble guanylyl cyclase (sGC) is a key enzyme involved in the production of the second messenger cGMP. Due its cardiovascular relevance, sGC has been the target of numerous drug discovery efforts leading to the development of many different activators and stimulators with pharmaceutical potential. One of such compounds is the sGC activator Cinaciguat (BAY 58-2667) which is in clinical trials for acute decompensated heart failure.

Results

We present here our latest structure-function studies related to sGC activation by different sGC activators. The activator complex structures reveal an intriguing mode of heme mimicry by these compounds. The observed activation conformational changes center around the αF helix that contains the H105 residue normally held in place by the heme moiety in the absence of the activators.

Conclusion

The structural insights gained from the complex structures could be used for further optimization and development of sGC activators.

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Authors and Affiliations

  1. Department of Biochemistry/RT500, Case Western Reserve University, Cleveland, OH, 44106, USA

    Focco van den Akker, Faye Martin, Vijay Kumar & Xiaolei Ma

  2. Cardiovascular Research, Bayer Schering Pharma AG, Wuppertal, D-42096, Germany

    Johannes-Peter Stasch & Martina Schaefer

  3. Department of Pharmacology and Physiology, New Jersey Medical School, U. Of Medicine and Dentistry of New Jersey, Newark, NJ, 07103, USA

    Padmamalini Baskaran & Annie Beuve

  4. Stanford Synchrotron Radiation Laboratory, Stanford University, Menlo Park, CA, 94025, USA

    Pete W van Dunten

Authors
  1. Focco van den Akker
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  2. Faye Martin
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  3. Vijay Kumar
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  4. Xiaolei Ma
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  5. Johannes-Peter Stasch
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  6. Martina Schaefer
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  7. Padmamalini Baskaran
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  8. Annie Beuve
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  9. Pete W van Dunten
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Corresponding author

Correspondence to Focco van den Akker.

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This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Cite this article

van den Akker, F., Martin, F., Kumar, V. et al. Structural insights into sGC activation by different activators. BMC Pharmacol 11 (Suppl 1), O11 (2011). https://doi.org/10.1186/1471-2210-11-S1-O11

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  • DOI: https://doi.org/10.1186/1471-2210-11-S1-O11

Keywords

  • Discovery Effort
  • Change Center
  • Guanylyl Cyclase
  • Decompensated Heart Failure
  • Acute Decompensated Heart Failure

BMC Pharmacology

ISSN: 1471-2210