Structure of a crystal form of human methemoglobin indicative of fiber formation

Abstract

Human methemoglobin was crystallized in a unique unit cell and its structure was solved by molecular replacement. The hexagonal unit cell has unit‐cell parameters a = b = 54.6, c = 677.4 Å, with symmetry consistent with space group P6122. The unit cell has the second highest aspect ratio of all unit cells contained in the PDB. The 12 molecules in the unit cell describe a right‐handed helical filament having no polarity, which is different from the filament composed of HbS fibers, which is the only other well characterized fiber of human hemoglobin. The filaments reported here can be related to canonical sickle‐cell hemoglobin filaments and to an alternative sickle‐cell filament deduced from fiber diffraction by slight modifications of intermolecular contacts.

Structural Studies on Molecular Interactions between Camel Peptidoglycan Recognition Protein, CPGRP-S, and Peptidoglycan Moieties N-Acetylglucosamine and N-Acetylmuramic Acid

“…The buried surface areas (31,32) . These values indicate that the buried areas of molecules A-B and C-D fall within the ranges associated with oligomerization of proteins (33) and are considerably larger than those observed between molecules in crystal packings (34). It may also be mentioned that of a total of 13 proline residues in CPGRP-S, nine were located at the interface.…”

Methemoglobin aggregation is modulated by the anti-sickling drug voxelotor

“…A) Model and high-resolution crystal structure of metHb in the R-state at pH 5.5; one cell unit contains 12 tetramers (3ODQ.pdb). B) Model adapted from [8] showing the effect of voxelotor: both drug binding to promote the R-state and protonation of surface histidine at low pH drive fiber formation. C) Effect of voxelotor on metHb particle formation measured by scattering at 700 nm, pH 5.5, 200mM sodium phosphate, 37 °C; blue includes drug; orange is control.…”

“…To determine the structure of metHb, Larson, et. al ., tested crystal growth at many pH values [8]. They found that the best crystals formed between pH = 4.5 to 5.5 and proposed that electrostatic interactions between β/β contacts would be optimal at low pH values and facilitate metHb polymer formation [8].…”

“…al ., tested crystal growth at many pH values [8]. They found that the best crystals formed between pH = 4.5 to 5.5 and proposed that electrostatic interactions between β/β contacts would be optimal at low pH values and facilitate metHb polymer formation [8]. These fibers only form under conditions where histidine is positively charged.…”

“…Figure 3A includes the crystal structure of metHb fibers with 12 hemoglobin tetramers arranged linearly in a single unit cell [8]. Larson and colleagues proposed that two histidines can become protonated at pH 5.5 creating positively charged side chains that interact through favorable electrostatics with the negatively charged Glu6 of a neighboring Hb tetramer, driving protein/protein docking interactions ( Figure 3B and figure 4 in [8]). MetHb fibers are distinct since the protein adopts the R-conformation in this single-strand fiber ( Figure 3A ).…”