Ligand Selectivity of Soluble Guanylyl Cyclase

  title={Ligand Selectivity of Soluble Guanylyl Cyclase},
  author={Emil Martin and Vladimir Berka and Elena P. Bogatenkova and Ferid Murad and Ah-lim Tsai},
  journal={Journal of Biological Chemistry},
  pages={27836 - 27845}
Although soluble guanylyl cyclase (sGC) functions in an environment in which O2, NO, and CO are potential ligands for its heme moiety, the enzyme displays a high affinity for only its physiological ligand, NO, but has a limited affinity for CO and no affinity for O2. Recent studies of a truncated version of the sGC β1-subunit containing the heme-binding domain (Boon, E. M., Huang, S H., and Marletta, M. A. (2005) Nat. Chem. Biol., 1, 53–59) showed that introduction of the hydrogen-bonding… 

Figures and Tables from this paper

Oxygen Binding and Redox Properties of the Heme in Soluble Guanylate Cyclase

It is proposed that the weak Fe2+-proximal His bond is a key determinant for the low O2 affinity of the heme moiety of soluble guanylate cyclase.

Incorporation of Tyrosine and Glutamine Residues into the Soluble Guanylate Cyclase Heme Distal Pocket Alters NO and O2 Binding*

It is found that the NO coordination state, NO dissociation, and enzyme activation were significantly affected by the presence of a tyrosine in the distal heme pocket; however, the stability of the reduced porphyrin and the proteins affinity for oxygen were unaltered, suggesting that atypical sGCs stabilize O2 binding by a hydrogen bonding network involving tyrosines and glutamine.

The Mechanism of Allosteric Regulation in Soluble Guanylate Cyclase

This dissertation describes experiments designed to uncover the molecular basis for signal transduction in sGC by NO and small molecule stimulators and shows that the coiled coil domain plays a pocket important in allostery and drug action.

YC-1 binding to the β subunit of soluble guanylyl cyclase overcomes allosteric inhibition by the α subunit.

YC-1 family compounds bind near the heme domain, overcoming the α subunit effect and inducing a heme pocket conformation with high affinity, which is proposed to be required for the full-length protein to achieve high catalytic activity.

Mechanism of NO binding to soluble guanylyl cyclase: implication for the second NO binding to the heme proximal site

This study used 15 NO and 14 NO and anaerobic sequential mixing-freeze quench EPR to unambiguously confirm that the heme Fe is the target of the second NO and predicts the kinetics of formation of a set of five-coordinate NO complexes with the ligand on either the distal or proximal site.

Mechanism of binding of NO to soluble guanylyl cyclase: implication for the second NO binding to the heme proximal site.

Computer modeling successfully predicts the kinetics of formation of a set of five-coordinate NO-sGC complex containing a proximal NO is formed after the binding of the second NO, and supports the selective release of NO from the distal side of the transient bis-NO-s GC complex.

Quaternary Structure Controls Ligand Dynamics in Soluble Guanylate Cyclase*

It is concluded that the α-subunit and the β1(191–619) domain exert structural strains on the heme domain that are likely involved in the transmission of the energy and relaxation toward the activated state after Fe2+-His bond breaking.

H-NOX domains display different tunnel systems for ligand migration.

Structure and Activation of Soluble Guanylyl Cyclase, the Nitric Oxide Sensor.

The molecular evolution of sGC, new molecular models, and the linked equilibria between sGC NO binding, drug binding, and catalytic activity are described and open the door for new drug discovery targeting sGC.

Dynamic Ligand Exchange in Soluble Guanylyl Cyclase (sGC)

It is proposed that conformational changes leading to sGC desensitization may be prevented by GTP binding to the catalytic site or by binding of an additional NO molecule to the proximal side of the heme.



A Functional Heme‐Binding Site of Soluble Guanylyl Cyclase Requires Intact N‐Termini of α1 and β1 Subunits

The purified enzyme truncated on α1 has a significantly reduced capacity to bind heme which explains the reduced NO sensitivity and the heme binding site of soluble guanylyl cyclase requires the presence of both subunits in full length to be able to bind wild-type quantities of heme and to be capable of mediating the NO-heme-induced stimulation.

Identification of Residues Crucially Involved in the Binding of the Heme Moiety of Soluble Guanylate Cyclase*

A signal transmission triad composed of histidine 105, tyrosine 135, and arginine 139 responsible for the enzyme activation by this compound and probably also for transducing changes in heme status and porphyrin geometry upon NO binding into alterations of sGC catalytic activity is postulated.

A molecular basis for NO selectivity in soluble guanylate cyclase

These data suggest that sGC uses a kinetic selection against O2; it is proposed that the O2 dissociation rate in the absence of this tyrosine is fast and that a stable O2 complex does not form.

Soluble guanylate cyclase from bovine lung: activation with nitric oxide and carbon monoxide and spectral characterization of the ferrous and ferric states.

Using a novel procedure, the enzyme has been purified to homogeneity from bovine lung with a heme content of approximately 1 heme/heterodimer, and .NO increases the Vmax of sGC by 100-200-fold, probably by interacting with aHeme moiety on the enzyme.

A constitutively activated mutant of human soluble guanylyl cyclase (sGC): Implication for the mechanism of sGC activation

It is proposed that the heme moiety through its coordination with His-105 of the β subunit acts as an endogenous inhibitor of sGC, releasing the restrictions imposed by binding of NO and allowing the formation of an optimally organized catalytic center in the heterodimer.

Crystal structure of an oxygen-binding heme domain related to soluble guanylate cyclases.

Comparison of the structure of the H-NOX domain in two different crystal forms suggests a mechanism whereby alteration in the degree of distortion of the heme group is coupled to changes on the molecular surface of the SOTA domain and potentially to changes in intermolecular interactions.

Nitric Oxide Binding to Prokaryotic Homologs of the Soluble Guanylate Cyclase β1 H-NOX Domain*

The heme cofactor in soluble guanylate cyclase (sGC) is a selective receptor for NO, an important signaling molecule in eukaryotes and three new members of this family have now been cloned and characterized, two proteins from Legionella pneumophila and one from Nostoc punctiforme.

Resonance raman characterization of the heme domain of soluble guanylate cyclase.

It is proposed that the absence of hydrogen-bond formation between a distal residue and exogenous ligands is physiologically relevant in lowering the oxygen affinity of heterodimeric sGC and, therefore, stabilizing the ferrous, active form of the enzyme under aerobic conditions.