Picosecond to second dynamics reveals a structural transition in Clostridium botulinum NO-sensor triggered by the activator BAY-41-2272

ACS Chem Biol. 2012 Dec 21;7(12):2046-54. doi: 10.1021/cb3003539. Epub 2012 Oct 2.


Soluble guanylate cyclase (sGC) is the mammalian endogenous nitric oxide (NO) receptor that synthesizes cGMP upon NO activation. In synergy with the artificial allosteric effector BAY 41-2272 (a lead compound for drug design in cardiovascular treatment), sGC can also be activated by carbon monoxide (CO), but the structural basis for this synergistic effect are unknown. We recorded in the unusually broad time range from 1 ps to 1 s the dynamics of the interaction of CO binding to full length sGC, to the isolated sGC heme domain β(1)(200) and to the homologous bacterial NO-sensor from Clostridium botulinum. By identifying all phases of CO binding in this full time range and characterizing how these phases are modified by BAY 41-2272, we show that this activator induces the same structural changes in both proteins. This result demonstrates that the BAY 41-2272 binding site resides in the β(1)(200) sGC heme domain and is the same in sGC and in the NO-sensor from Clostridium botulinum.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism*
  • Clostridium botulinum / metabolism*
  • Guanylate Cyclase / metabolism
  • Ligands
  • Molecular Sequence Data
  • Nitric Oxide / chemistry
  • Nitric Oxide / metabolism*
  • Protein Conformation
  • Pyrazoles / pharmacology*
  • Pyridines / pharmacology*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Sequence Homology, Amino Acid
  • Soluble Guanylyl Cyclase


  • 3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
  • Bacterial Proteins
  • Ligands
  • Pyrazoles
  • Pyridines
  • Receptors, Cytoplasmic and Nuclear
  • Nitric Oxide
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase