Structure of a ligand-binding intermediate in wild-type carbonmonoxy myoglobin

Small molecules such as NO, O-2, CO or H-2 are important biological ligands that bind to metalloproteins to function crucially in processes such as si gnal transduction, respiration and catalysis. A key issue for understanding the regulation of reaction mechanisms in these systems is whether ligands gain access to the binding sites through specific channels and docking site s, or by random diffusion through the protein matrix. A model system for st udying this issue is myoglobin, a simple haem protein. Myoglobin has been s tudied extensively by spectroscopy, crystallography, computation and theory (1-11). It serves as an aid to oxygen diffusion but also binds carbon mono nide, a byproduct of endogenous haem catabolism. Molecular dynamics simulat ions(3-5), random mutagenesis(6) and flash photolysis studies(7-10) indicat e that ligand migration occurs through a limited number of pathways involvi ng docking sites. Here we report the 1.4 Angstrom resolution crystal struct ure of a ligand-binding intermediate in carbonmonoxy myoglobin that may hav e far-reaching implications for understanding the dynamics of ligand bindin g and catalysis.