Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 9, Pages 4741-4748Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1913663117
Keywords
hemoglobin; ligand migration; X-ray crystallography; allostery
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Funding
- Japan Society for the Promotion of Science KAKENHI Grants [JP 16K07326, JP 17H06372, JP 19K06601, JP 19H05779]
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Hemoglobin is one of the best-characterized proteins with respect to structure and function, but the internal ligand diffusion pathways remain obscure and controversial. Here we captured the CO migration processes in the tense (T), relaxed (R), and second relaxed (R2) quaternary structures of human hemoglobin by crystallography using a high-repetition pulsed laser technique at cryogenic temperatures. We found that in each quaternary structure, the photo-dissociated CO molecules migrate along distinct pathways in the a and beta subunits by hopping between the internal cavities with correlated side chain motions of large nonpolar residues, such as alpha 14Trp(A12), alpha 105Leu(G12), beta 15Trp(A12), and beta 71Phe(E15). We also observe electron density evidence for the distal histidine [alpha 58/beta 63His(E7)] swing-out motion regardless of the quaternary structure, although less evident in alpha subunits than in beta subunits, suggesting that some CO molecules have escaped directly through the E7 gate. Remarkably, in T-state Fe(II)-Ni(II) hybrid hemoglobins in which either the alpha or beta subunits contain Ni(II) heme that cannot bind CO, the photodissociated CO molecules not only dock at the cavities in the original Fe(II) subunit, but also escape from the protein matrix and enter the cavities in the adjacent Ni(II) subunit even at 95 K, demonstrating the high gas permeability and porosity of the hemoglobin molecule. Our results provide a comprehensive picture of ligand movements in hemoglobin and highlight the relevance of cavities, nonpolar residues, and distal histidines in facilitating the ligand migration.
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