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Myoglobin cavities provide interior ligand pathway.

ABSTRACT: The myoglobin protein binds oxygen and catalyzes NO oxidation. As a key model protein, its dynamics have been well studied by spectroscopy and by crystallography as well as by simulation. Nonetheless, visualization of the mechanism of movement of ligands within myoglobin has been difficult. Coordinates of the A1 and A3 taxonomic spectral states of myoglobin from the 1 A crystal structure (1a6g) are generated as consistent sets of correlated clusters of residues with A or B crystal alternates. Analysis of cavities in these A1 and A3 conformations clarifies the pathway of ligand motion from distal entry through interior movement to the proximal side of the heme. Cavities opened up by buried alternate conformations link the distal to the proximal side of the heme. Structural conservation highlights the relevance of this pathway to human neuroglobin. Cavity migration via myoglobin crystal alternates provides a specific link of protein structure to protein dynamics and protein function and demonstrates the relevance of substates (discrete disorder) to function for all proteins.

SUBMITTER: Teeter MM

PROVIDER: S-EPMC2286717 | biostudies-literature | 2004 Feb

REPOSITORIES: biostudies-literature

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Myoglobin cavities provide interior ligand pathway.

Teeter Martha M MM

Protein science : a publication of the Protein Society 20040201 2

The myoglobin protein binds oxygen and catalyzes NO oxidation. As a key model protein, its dynamics have been well studied by spectroscopy and by crystallography as well as by simulation. Nonetheless, visualization of the mechanism of movement of ligands within myoglobin has been difficult. Coordinates of the A1 and A3 taxonomic spectral states of myoglobin from the 1 A crystal structure (1a6g) are generated as consistent sets of correlated clusters of residues with A or B crystal alternates. An ...[more]

PMID: 14739317

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Project description:The free volume in the active site of human HbA plays a crucial role in governing the bimolecular rates of O(2), CO, and NO binding, the fraction of geminate ligand recombination, and the rate of NO dioxygenation by the oxygenated complex. We have decreased the size of the distal pocket by mutating Leu(B10), Val(E11), and Leu(G8) to Phe and Trp and that of other more internal cavities by filling them with Xe at high gas pressures. Increasing the size of the B10 side chain reduces bimolecular rates of ligand binding nearly 5000-fold and inhibits CO geminate recombination due to both reduction of the capture volume in the distal pocket and direct steric hindrance of Fe-ligand bond formation. Phe and Trp(E11) mutations also cause a decrease in distal pocket volume but, at the same time, increase access to the Fe atom because of the loss of the γ2 CH(3) group of the native Val(E11) side chain. The net result of these E11 substitutions is a dramatic increase in the rate of geminate recombination because dissociated CO is sequestered close to the Fe atom and can rapidly rebind without steric resistance. However, the bimolecular rate constants for binding of ligand to the Phe and Trp(E11) mutants are decreased 5-30-fold, because of a smaller capture volume. Geminate and bimolecular kinetic parameters for Phe and Trp(G8) mutants are similar to those for the native HbA subunits because the aromatic rings at this position cause little change in distal pocket volume and because ligands do not move past this position into the globin interior of wild-type HbA subunits. The latter conclusion is verified by the observation that Xe binding to the α and β Hb subunits has little effect on either geminate or bimolecular ligand rebinding. All of these experimental results argue strongly against alternative ligand migration pathways that involve movements through the protein interior in HbA. Instead, ligands appear to enter through the His(E7) gate and are captured directly in the distal cavity.

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Myoglobin cavities provide interior ligand pathway.

Publications

Myoglobin cavities provide interior ligand pathway.

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