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Biochemistry. 2018 Aug 14;57(32):4788-4802. doi: 10.1021/acs.biochem.8b00542. Epub 2018 Jul 27.

Nitrosyl Myoglobins and Their Nitrite Precursors: Crystal Structural and Quantum Mechanics and Molecular Mechanics Theoretical Investigations of Preferred Fe -NO Ligand Orientations in Myoglobin Distal Pockets.

Author information

1
Price Family Foundation Institute of Structural Biology and Department of Chemistry and Biochemistry , University of Oklahoma , 101 Stephenson Parkway , Norman , Oklahoma 73019 , United States.
2
Department of Chemistry and Chemical Biology , Stevens Institute of Technology , Castle Point on Hudson , Hoboken , New Jersey 07030 , United States.
3
Heart, Lung, Blood and Vascular Medicine Institute , University of Pittsburgh School of Medicine , 3550 Terrace Street , Pittsburgh , Pennsylvania 15261 , United States.
4
Department of Pharmacology and Chemical Biology , University of Pittsburgh , 200 Lothrop Street , Pittsburgh , Pennsylvania 15213 , United States.

Abstract

The globular dioxygen binding heme protein myoglobin (Mb) is present in several species. Its interactions with the simple nitrogen oxides, namely, nitric oxide (NO) and nitrite, have been known for decades, but the physiological relevance has only recently become more fully appreciated. We previously reported the O-nitrito mode of binding of nitrite to ferric horse heart wild-type (wt) MbIII and human hemoglobin. We have expanded on this work and report the interactions of nitrite with wt sperm whale (sw) MbIII and its H64A, H64Q, and V68A/I107Y mutants whose dissociation constants increase in the following order: H64Q < wt < V68A/I107Y < H64A. We also report their X-ray crystal structures that reveal the O-nitrito mode of binding of nitrite to these derivatives. The MbII-mediated reductions of nitrite to NO and structural data for the wt and mutant MbII-NOs are described. We show that their FeNO orientations vary with distal pocket identity, with the FeNO moieties pointing toward the hydrophobic interiors when the His64 residue is present but toward the hydrophilic exterior when this His64 residue is absent in this set of mutants. This correlates with the nature of H-bonding to the bound NO ligand (nitrosyl O vs N atom). Quantum mechanics and hybrid quantum mechanics and molecular mechanics calculations help elucidate the origin of the experimentally preferred NO orientations. In a few cases, the calculations reproduce the experimentally observed orientations only when the whole protein is taken into consideration.

PMID:
29999305
PMCID:
PMC6474360
[Available on 2019-08-14]
DOI:
10.1021/acs.biochem.8b00542

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