title: Picosecond to second dynamics reveals a structural transition in Clostridium botulinum NO-sensor triggered by the activator BAY-41-2272.
abstract: 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.
authors.affiliation: Laboratoire d'Optique et Biosciences, INSERM U696, CNRS UMR 7645, Ecole Polytechnique, 91128 Palaiseau Cedex, France.
authors.forename: Byung-Kuk
authors.initials: BK
authors.lastname: Yoo
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lamarre
authors.forename: Fabrice
authors.initials: F
authors.lastname: Rappaport
authors.forename: Pierre
authors.initials: P
authors.lastname: Nioche
authors.forename: C S
authors.initials: CS
authors.lastname: Raman
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Martin
authors.forename: Michel
authors.initials: M
authors.lastname: Negrerie
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D003014:Clostridium botulinum / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism; D008024:Ligands; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D000071756:Soluble Guanylyl Cyclase
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D001426:Bacterial Proteins; D008024:Ligands; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase