8885dc05_157-1898/12/038:55 AM Page164mac78mac78:385 164 Part I Structure and Catalysis of the ion pairs that stabilize the T' state are broken and some new ones are formed Max Perutz proposed that the T-R transition triggered by changes in the positions of key amino acid side chains surrounding the heme In the T state, the porphyrin is slightly puckered, causing the heme iron to protrude somewhat on the proximal His (His F8) side The binding of O, causes the heme to assume a more planar conformation, shifting the position of the proxi- mal His and the attached F helix (Fig. 5-11). These changes lead to adjustments in the ion pairs at the a,B Hemoglobin Binds Oxygen Cooperatively Hemoglobin must bind oxygen efficiently in the lungs, FIGURE 5-8 Dominant interactions between hemoglobin subunits. where the pO is about 13.3 kPa, and release oxygen in In this representation, a subunits are light and B subunits are dark the tissues, where the pO2 is about 4 kPa. Myoglobin, The strongest subunit interactions(highlighted)occur between unlike or any protein that binds oxygen with a hyperbolic bind subunits. When oxygen binds, the a,B, contact changes little, but ing curve, would be ill-suited to this function, for the there is a large change at the a1B2 contact, with several ion pairs bro. reason illustrated in Figure 5-12. A protein that bound ken(PDB ID 1HGA) Asp FG1 The quaternary structure of hemoglobin features c subunit Lys C5 strong interactions between unlike subunits. The a B, His hc3 interface(and its a,B, counterpart) involves more than 30 residues, and its interaction is sufficiently strong that although mild treatment of hemoglobin with urea tends to cause the tetramer to disassemble into aB dimers, these dimers remain intact. The a B2(and a2B1) inter face involves 19 residues (Fig. 5-8). Hydrophobic in- teractions predominate at the interfaces, but there are also many hydrogen bonds and a few ion pairs(some- times referred to as salt bridges), whose importance is Hemoglobin Undergoes a Structural Change Asp His* NH3 on Binding Oxygen FGI H Arg+. Asp X-ray analysis has revealed two major conformations of hemoglobin: the R state and the T state. Although oxy HC3 H9 gen binds to hemoglobin in either state, it has a signif- NH3 coo icantly higher affinity for hemoglobin in the R state. Oxy- H9 HC3 gen binding stabilizes the R state. When oxygen is Hist As COO absent experimentally, the t state is more stable and is HC3 FG1 thus the predominant conformation of deoxyhemoglo bin. T and R originally denoted"tense"and"relaxed FIGURE 5-9 Some ion pairs that stabilize the T state of deoxyhe- respectively, because the T state is stabilized by a moglobin.(a)A close-up view of a portion of a deoxyhemoglobin greater number of ion pairs, many of which lie at the molecule in the t state(PDB ID 1HGA) Interactions between the ion aiB2(and ceBi interface(Fig. 5-9). The binding of O pairs His HC3 and Asp FGI of the B subunit(blue) and between Ly to a hemoglobin subunit in the T state triggers a change C5 of the a subunit (gray) and His HC3(its a-carboxyl group) of the in conformation to the R state. When the entire protein B subunit hown with dashed lines. (Recall that HC3 is the undergoes this transition, the structures of the individ carboxyl-terminal residue of the B subunit )(b) The interactions be- ual subunits change little, but the aB subunit pairs slide tween these ion pairs, and between others not shown in(a),are past each other and rotate, narrowing the pocket be- schematized in this representation of the extended polypeptide chains tween the B subunits(Fig. 5-10). In this process, some of hemoglobinof the ion pairs that stabilize the T state are broken and some new ones are formed. Max Perutz proposed that the T n R transition is triggered by changes in the positions of key amino acid side chains surrounding the heme. In the T state, the porphyrin is slightly puckered, causing the heme iron to protrude somewhat on the proximal His (His F8) side. The binding of O2 causes the heme to assume a more planar conformation, shifting the position of the proxi￾mal His and the attached F helix (Fig. 5–11). These changes lead to adjustments in the ion pairs at the
12 interface. Hemoglobin Binds Oxygen Cooperatively Hemoglobin must bind oxygen efficiently in the lungs, where the pO2 is about 13.3 kPa, and release oxygen in the tissues, where the pO2 is about 4 kPa. Myoglobin, or any protein that binds oxygen with a hyperbolic bind￾ing curve, would be ill-suited to this function, for the reason illustrated in Figure 5–12. A protein that bound 164 Part I Structure and Catalysis a1 a2 b1 b2 FIGURE 5–8 Dominant interactions between hemoglobin subunits. In this representation,
subunits are light and  subunits are dark. The strongest subunit interactions (highlighted) occur between unlike subunits. When oxygen binds, the
11 contact changes little, but there is a large change at the
12 contact, with several ion pairs bro￾ken (PDB ID 1HGA). (a) a subunit b subunit Asp FG1 His HC3 Lys C5 COO COO COO Arg+ Lys+ Asp Arg+ Asp Lys+ His+ His+ Asp Asp HC3 FG1 HC3 H9 HC3 FG1 C5 H9 HC3 C5 COO NH3 b2 b1 a2 a1 (b) + NH3 + NH3 + NH3 + FIGURE 5–9 Some ion pairs that stabilize the T state of deoxyhe￾moglobin. (a) A close-up view of a portion of a deoxyhemoglobin molecule in the T state (PDB ID 1HGA). Interactions between the ion pairs His HC3 and Asp FG1 of the  subunit (blue) and between Lys C5 of the
subunit (gray) and His HC3 (its
-carboxyl group) of the  subunit are shown with dashed lines. (Recall that HC3 is the carboxyl-terminal residue of the  subunit.) (b) The interactions be￾tween these ion pairs, and between others not shown in (a), are schematized in this representation of the extended polypeptide chains of hemoglobin. The quaternary structure of hemoglobin features strong interactions between unlike subunits. The
11 interface (and its
22 counterpart) involves more than 30 residues, and its interaction is sufficiently strong that although mild treatment of hemoglobin with urea tends to cause the tetramer to disassemble into
 dimers, these dimers remain intact. The
12 (and
21) inter￾face involves 19 residues (Fig. 5–8). Hydrophobic in￾teractions predominate at the interfaces, but there are also many hydrogen bonds and a few ion pairs (some￾times referred to as salt bridges), whose importance is discussed below. Hemoglobin Undergoes a Structural Change on Binding Oxygen X-ray analysis has revealed two major conformations of hemoglobin: the R state and the T state. Although oxy￾gen binds to hemoglobin in either state, it has a signif￾icantly higher affinity for hemoglobin in the R state. Oxy￾gen binding stabilizes the R state. When oxygen is absent experimentally, the T state is more stable and is thus the predominant conformation of deoxyhemoglo￾bin. T and R originally denoted “tense” and “relaxed,” respectively, because the T state is stabilized by a greater number of ion pairs, many of which lie at the
12 (and
21) interface (Fig. 5–9). The binding of O2 to a hemoglobin subunit in the T state triggers a change in conformation to the R state. When the entire protein undergoes this transition, the structures of the individ￾ual subunits change little, but the
 subunit pairs slide past each other and rotate, narrowing the pocket be￾tween the  subunits (Fig. 5–10). In this process, some 8885d_c05_157-189 8/12/03 8:55 AM Page 164 mac78 mac78:385_REB: