8885ac05157-1898/12/038:55 AM Page165mac78mac78:385p Chapter 5 Protein Function His hc3 AC T state R state FIGURE 5-10 The T-R transition (PDB ID 1HGA and 5-9. The transition from the t state to the r state shifts the subunit hese depictions of deoxyhemoglobin, as in Figure 5-9, the B subunits irs substantially, affecting certain ion pairs. Most noticeab ly, the His re blue and the a subunits are gray. Positively charged side chains HC3 residues at the carboxyl termini of the B subunits, which are and chain termini involved in ion pairs are shown in blue, their neg. volved in ion pairs in the T state, rotate in the r state toward the cen tively charged partners in red. The Lys C5 of each a subunit and Asp ter of the molecule, where they are no longer in ion pairs. Another FG1 of each B subunit are visible but not labeled(compare Fig. 5-9a). dramatic result of the T-R transition is a narrowing of the pocket Note that the molecule is oriented slightly differently than O2 with high affinity would bind it efficiently in the lungs An allosteric protein is one in which the binding but would not release much of it in the tissues. If the of a ligand to one site affects the binding properties of protein bound oxygen with a sufficiently low affinity to another site on the same protein. The term"allosteric release it in the tissues, it would not pick up much oxy- derives from the Greek allos, "other, " and stereos gen in the lungs “ solid”or“ shape." Allosteric proteins are those having Hemoglobin solves the problem by undergoing a" other shapes, " or conformations, induced by the bind transition from a low-affinity state (the T state) to a ing of ligands referred to as modulators. The conforma high-affinity state(the R state)as more Oe molecules tional changes induced by the modulator(s) intercon- are bound. As a result, hemoglobin has a hybrid s- vert more-active and less-active forms of the protein. shaped, or sigmoid, binding curve for oxygen (Fig. The modulators for allosteric proteins may be either 12). A single-subunit protein with a single ligand- inhibitors or activators. When the normal ligand and binding site cannot produce a sigmoid binding curve- even if binding elicits a conformational change- because each molecule of ligand binds independently and cannot affect the binding of another molecule. In Leu Hem contrast, O, binding to individual subunits of hemo- globin can alter the affinity for O2 in adjacent subunits The first molecule of O2 that interacts with deoxyhe- moglobin binds weakly, because it binds to a subunit in the T state. Its binding, however, leads to confor- mational changes that are communicated to adjacent Helix F subunits, making it easier for additional molecules of Leu F4 O to bind. In effect the t-R transition occurs more T state readily in the second subunit once O, is bound to the first subunit. The last (fourth) O2 molecule binds to a FIGURE 5-11 Changes in conformation near heme on O2 binding heme in a subunit that is already in the R state, and to deoxyhemoglobin (Derived from PDB ID 1HGA and 1BBB)The hence it binds with much higher affinity than the first shift in the position of the F helix when heme binds O2 is thought to be one of the adjustments that triggers the T-R transitionO2 with high affinity would bind it efficiently in the lungs but would not release much of it in the tissues. If the protein bound oxygen with a sufficiently low affinity to release it in the tissues, it would not pick up much oxy￾gen in the lungs. Hemoglobin solves the problem by undergoing a transition from a low-affinity state (the T state) to a high-affinity state (the R state) as more O2 molecules are bound. As a result, hemoglobin has a hybrid S￾shaped, or sigmoid, binding curve for oxygen (Fig. 5–12). A single-subunit protein with a single ligand￾binding site cannot produce a sigmoid binding curve— even if binding elicits a conformational change— because each molecule of ligand binds independently and cannot affect the binding of another molecule. In contrast, O2 binding to individual subunits of hemo￾globin can alter the affinity for O2 in adjacent subunits. The first molecule of O2 that interacts with deoxyhe￾moglobin binds weakly, because it binds to a subunit in the T state. Its binding, however, leads to confor￾mational changes that are communicated to adjacent subunits, making it easier for additional molecules of O2 to bind. In effect, the T n R transition occurs more readily in the second subunit once O2 is bound to the first subunit. The last (fourth) O2 molecule binds to a heme in a subunit that is already in the R state, and hence it binds with much higher affinity than the first molecule. An allosteric protein is one in which the binding of a ligand to one site affects the binding properties of another site on the same protein. The term “allosteric” derives from the Greek allos, “other,” and stereos, “solid” or “shape.” Allosteric proteins are those having “other shapes,” or conformations, induced by the bind￾ing of ligands referred to as modulators. The conforma￾tional changes induced by the modulator(s) intercon￾vert more-active and less-active forms of the protein. The modulators for allosteric proteins may be either inhibitors or activators. When the normal ligand and Chapter 5 Protein Function 165 His HC3 His HC3 His HC3 a1 a2 b1 b2 a1 a2 b1 b2 T state R state FIGURE 5–10 The T n R transition. (PDB ID 1HGA and 1BBB) In these depictions of deoxyhemoglobin, as in Figure 5–9, the  subunits are blue and the
subunits are gray. Positively charged side chains and chain termini involved in ion pairs are shown in blue, their neg￾atively charged partners in red. The Lys C5 of each
subunit and Asp FG1 of each  subunit are visible but not labeled (compare Fig. 5–9a). Note that the molecule is oriented slightly differently than in Figure 5–9. The transition from the T state to the R state shifts the subunit pairs substantially, affecting certain ion pairs. Most noticeably, the His HC3 residues at the carboxyl termini of the  subunits, which are in￾volved in ion pairs in the T state, rotate in the R state toward the cen￾ter of the molecule, where they are no longer in ion pairs. Another dramatic result of the T n R transition is a narrowing of the pocket between the  subunits. T state R state Val FG5 Heme O2 Leu FG3 Helix F Leu F4 His F8 FIGURE 5–11 Changes in conformation near heme on O2 binding to deoxyhemoglobin. (Derived from PDB ID 1HGA and 1BBB.) The shift in the position of the F helix when heme binds O2 is thought to be one of the adjustments that triggers the T n R transition. 8885d_c05_157-189 8/12/03 8:55 AM Page 165 mac78 mac78:385_REB: