Role of Heme Iron Coordination and Protein Structure in the Dynamics and Geminate Rebinding of Nitric Oxide to the H93G Myoglobin Mutant

Négrerie, Michel; Kruglik, Sergei G.; Lambry, Jean−Christophe; Vos, Marten H.; Martin, Jean−Louis; Franzen, Stefan

doi:10.1074/jbc.m513375200

Cited by 30 publications

(40 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Remarkably, the rebinding of NO to the heme alone in solution is also mono-exponential (7.5 ps) but with a constant base line (8%) that corresponds to NO escape into the solvent (46,47). Thus, a time constant of ϳ7 ps for NO rebinding to the 4-coordinate heme after dissociation (either thermal or photoinduced) seems to be the lower limit for this barrierless process when no protein structure is involved, in agreement with calculations (16,48) and with temperature-dependent rebinding measurements (42).…”

Section: Discussionsupporting

confidence: 69%

“…It is noteworthy that, despite the efficient and fast geminate recombination, the k off value for 5c-NO AXCP (4.1 ϫ 10 Ϫ4 s Ϫ1 ) is of the same order of magnitude as 5c-NO heme protein complexes such as sGC ( (16). The high geminate recombination efficiency imposed by the proximal heme environment of AXCP implies that the typical k off value is due to an elevated value of k 1 .…”

mentioning

confidence: 99%

“…This so-called trans effect is due to a weakening of the axial Fe-His bond caused by the trans-coordination of NO and is governed by protein structure (15). In 5c-NO species, the probability of fast NO rebinding after dissociation (either thermal or photo-induced) is increased (16) and tends to a single phase as observed in sGC (10). In sGC, the breaking of the proximal Fe-His bond in the resting state of the enzyme triggers the catalytic activity for cGMP production, whereas in AXCP the role of the proximal bond breaking and formation of a 5c-NO complex in a second order reaction (17,18) is not known.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Molecular Basis for Nitric Oxide Dynamics and Affinity with Alcaligenes xylosoxidans Cytochrome c´

Kruglik

Lambry

Cianetti

et al. 2007

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The bacterial heme protein cytochrome c from Alcaligenes xylosoxidans (AXCP) reacts with nitric oxide (NO) to form a 5-coordinate ferrous nitrosyl heme complex. The crystal structure of ferrous nitrosyl AXCP has previously revealed that NO is bound in an unprecedented manner on the proximal side of the heme. To understand how the protein structure of AXCP controls NO dynamics, we performed absorption and Raman timeresolved studies at the heme level as well as a molecular computational dynamics study at the entire protein structure level. We found that after NO dissociation from the heme iron, the structure of the proximal heme pocket of AXCP confines NO close to the iron so that an ultrafast (7 ps) and complete (99 ؎ 1%) geminate rebinding occurs, whereas the proximal histidine does not rebind to the heme iron on the timescale of NO geminate rebinding. The distal side controls the initial NO binding, whereas the proximal heme pocket controls its release. These dynamic properties allow the trapping of NO within the protein core and represent an extreme behavior observed among heme proteins.Nitric oxide (NO) acts as a second messenger in several physiological systems (1, 2), is involved in the production of several cytotoxic chemical species and nitrosative stress (3), and appears as an intermediate in the denitrification process (4). Cells have, thus, developed numerous heme proteins whose diverse functions involve nitric oxide binding and/or release. In some bacteria heme sensors were recently discovered (5) with a femtomolar affinity for NO, whereas cytochromes cЈ able to bind NO are found in many nitrogen-fixing, denitrifying, and photosynthetic bacteria (6). Although the physiological role the bacterial cytochrome cЈ from Alcaligenes xylosoxidans (AXCP) 2 is not yet established, the homologous cytochrome cЈ from Rhodobacter capsulatus has been shown to increase the resistance of this bacteria against NO toxicity (7,8). Thus, the bacterial cytochromes cЈ are inferred to disclose a particular behavior regarding NO dynamics and affinity. How heme proteins interact with NO and control its reactivity is ultimately related to their structure and the heme surroundings. A wide range of affinity and kinetic constants can be observed that correlates with the molecular dynamics of NO within the protein core. A striking example of this diversity is offered when comparing the NO dynamics governed by the enzyme NO synthase (9), the endogenous cellular source, and the NO receptorsoluble guanylate cyclase (10) (sGC) whose heme cofactor has a somewhat opposite role. Nitrosylated heme proteins usually form 6-coordinate complexes having histidine and NO as axial ligands at the proximal and distal sides of the heme, respectively (6c-NO-His), but some become 5-coordinate (5c) with NO (5c-NO) like sGC (11, 12) and AXCP (13,14). These latter proteins have an overall structure that presumably controls the strain upon the proximal histidine. Although sGC and AXCP possess different sequences and tertiary structures, they share the pro...

show abstract

Section: Discussionsupporting

confidence: 69%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Molecular Basis for Nitric Oxide Dynamics and Affinity with Alcaligenes xylosoxidans Cytochrome c´

Kruglik

Lambry

Cianetti

et al. 2007

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Met80 rebinding involves at least two electronic states: 1,4,11,20 the ground state singlet (s), associated with the bonded state, and the quintet (q), associated with the unbonded state. In this work, the classical CHARMM force field in the heme pocket has been extended by incorporating ab initio PES calculations.…”

Section: ■ Methodsmentioning

confidence: 99%

Dynamics of Methionine Ligand Rebinding in Cytochrome c

2012

View full text Add to dashboard Cite

Geminate recombination of the methionine ligand to the heme iron in ferrous cytochrome c protein following photodissociation displays rich kinetics. It is of particular interest to develop an understanding of fast and slow rebinding time scales, observed in experimental studies, in terms of features of the underlying complex energy landscape. The classical empirical force field in the heme pocket has been extended by incorporating ab initio potential energy surface calculations representing the ground singlet state and quintet state associated with methionine bond breaking and rebinding. An algorithm based on the Landau−Zener nonadiabatic transition theory has been employed to model the electronic surface hopping between two spin states during the process of ligand dissociation and recombination. Multiple conformational substates of the dissociated methionine ligand are found to participate in the reaction dynamics. Varying time scales for interconversion between substates lead to a mechanism elucidating the fast and slow rebinding time scales. The reaction system may be understood in terms of a two-dimensional reaction coordinate distinctly separated from the coupled bath of surrounding protein and solvent degrees of freedom. Insights into the reaction dynamics provided by this study lead to suggestions for future experiments to further probe the role of dynamic heterogeneity in the kinetics of ligand−protein binding. ■ INTRODUCTIONGeminate recombination of axial ligands to the iron atom in heme proteins, as one of the key steps of protein global structural dynamics and allostery, has been of great interest and widely studied both experimentally and theoretically in the past decades. Many of those studies have been dedicated to diatomic axial ligands, such as CO, NO, and O 2 in globins.1−27 From those studies, a deep and general understanding of protein dynamics, in terms of transitions between conformational substates, has developed and formed the foundation for modern "energy landscape" theories of protein dynamics and thermodynamics. In spite of this success, a rigorous understanding of molecular reaction dynamics for ligand rebinding in myoglobin has proven elusive. The Agmon−Hopfield 8 and Champion-Srajer 28,29 models of ligand rebinding define specific reaction coordinates for the rebinding process but also include an undefined protein coordinate as an essential component of the multidimensional reaction coordinate in addition to the surrounding bath. Although heme−ligand dissociation in heme proteins usually does not occur under normal conditions, heme−ligand bond breaking and rebinding take place during the process of internal and external ligand switching or competition in neuroglobin 30,31 as well as in a specific group of heme-based sensor proteins such as Ec DOS, DOSH, and CooA. 7,32,33 Understanding the kinetics and thermodynamics of internal ligand binding is essential to our knowledge of the composition and function of these heme proteins.Cytochrome c (cyt c) (Figure 1) is an essential ...

show abstract

“…Therefore, the amine nitrogen and heme iron cannot keep the optimal distance and the angle (C-N-Fe) to form an MI complex. A previous study reported that the potential energy of coordinate binding between the heme iron of myoglobin and nitric oxide depends on the distance (Negrerie et al, 2006). The potential energy reached the maximum at a distance of approximately 1.8 Å and then decreased dramatically according to dissociation between the heme iron and nitric oxide.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Mechanism-Based Inhibition of CYP 3A4 by a Series of Fluoroquinolone Antibacterial Agents

Watanabe

Takakusa

Kimura

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

A series of fluoroquinolone compounds (compounds 1-9), which contain a common quinolone scaffold, inactivated the metabolic activity of CYP3A. The purpose of this study was to identify mechanism-based inhibition (MBI) among these fluoroquinolone compounds by metabolite profiling to elucidate the association of the substructure and MBI potential. Reversibility of MBI after incubation with potassium ferricyanide differed among the test compounds. Representative quasi-irreversible inhibitors form a metabolite-intermediate (MI) complex with the heme of CYP3A4 according to absorption analysis. Metabolite profiling identified the cyclopropane ring-opened metabolites from representative irreversible inhibitors, suggesting irreversible binding of the carboncentered radical species with CYP3A4. On the other hand, the oxime form of representative quasi-irreversible inhibitors was identified, suggesting generation of a nitroso intermediate that could form the MI complex. Metabolites of compound 10 with a methyl group at the carbon atom at the root of the amine moiety of compound 8 include the oxime form, but compound 10 did not show quasiirreversible inhibition. The docking study with CYP3A4 suggested that a methyl moiety introduced at the carbon atom at the root of the primary amine disrupts formation of the MI complex between the heme and the nitroso intermediate because of steric hindrance. This study identified substructures of fluoroquinolone compounds associated with the MBI mechanism; introduction of substituted groups inducing steric hindrance with the heme of P450 can prevent formation of an MI complex. Our series of experiments may be broadly applicable to prevention of MBI at the drug discovery stage.

show abstract

Role of Heme Iron Coordination and Protein Structure in the Dynamics and Geminate Rebinding of Nitric Oxide to the H93G Myoglobin Mutant

Cited by 30 publications

References 56 publications

Molecular Basis for Nitric Oxide Dynamics and Affinity with Alcaligenes xylosoxidans Cytochrome c´

Molecular Basis for Nitric Oxide Dynamics and Affinity with Alcaligenes xylosoxidans Cytochrome c´

Dynamics of Methionine Ligand Rebinding in Cytochrome c

Analysis of Mechanism-Based Inhibition of CYP 3A4 by a Series of Fluoroquinolone Antibacterial Agents

Contact Info

Product

Resources

About