lec8 - !"#$%&" (...

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Unformatted text preview: !"#$%&" ( )"*+,-+./0 1"2 3+0#"4$5 Ligand binding fundamentally important in biochemical phenomena. Heme (Fe protoporphyrin IX) in myoglobin (Mb) and hemoglobin (Hb) binds O2 reversibly, without oxidation of the heme Fe +2 which is required for O2 binding. Mb and Hb's structures and ligand binding properties have evolved differently for the different functions of the two proteins, and the structure-function relationships are very well understood. Mb is monomeric, 1 O2 binding site per molecule, hyperbolic binding curve (no cooperativity). Hb is tetrameric, 4 O2 binding sites per molecule, sigmoid binding curve indicative of cooperative ligand binding (structural communication between different binding sites by conformational changes). Hb is thus an allosteric protein. 1"2 3+0#"4$5 Hb is an allosteric protein. R state ("oxy" conformation, high O2 binding afFnity) stabilized by O2 binding (O2 is a homotropic effector) T state ("deoxy" conformation, low O2 binding afFnity) stabilized by binding of protons (H+), CO2, and/or 2,3-bisphosphoglycerate (2,3-BPG) (all heterotropic effectors, allosteric inhibitors of O2 binding) Allosteric regulation of O2 binding to Hb is important to enhance the ability of Hb to RELEASE O2 in the tissues. 2,3-BPG is needed in human erythrocytes (red blood cells) to reduce O2 binding afFnity enough to get effective release of O2 in tissues. 2,3-BPG binds in central cavity of Hb in the T state (stoichiometry 1 BPG/Hb tetramer). etal Hb (Hb) has different quaternary structure from adult HbA (Hb is 2 2; HbA is 2 2) Sequence difference between and reduces Hb's afFnity for 2,3- BPG, thus increasing its afFnity for O2 under physiological conditions. !"6&0/0, 7.8"#9:"5 Terminology: ligand, fractional saturation, prosthetic group, cooperativity, protomer, binding site, allosteric (allosteric site, allosteric effector, allosteric regulation) BrieFy describe the tertiary structure of Mb and Hb subunits (the "globin fold"), explain how the helices are designated, and the roles of the proximal and distal His residues in heme and oxygen binding. Write a general protein-ligand binding/dissociation reaction in both the association and dissociation directions. What is the mathematical relationship between the association and dissociation equilibrium constants? Describe how and where in the structure of Mb and Hb O2 binds, including roles of protein functional groups and heme, and the oxidation state of the heme e required for O2 binding. Know how to interpret the O2 binding curves [Y (fractional saturation) vs. pO2], i.e NON cooperative ligand binding to a protein or cooperative ligand binding and explain what is meant by cooperativity. On both curves, indicate the value of P50, the pO2 at which fractional saturation of protein with O2 is 0.5. In what part of the cooperative binding curve (what part of the [ligand] concentration range) is protein predominantly in conformation with low ligand...
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lec8 - !"#$%&" (...

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