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(a) The diagram below on the right-hand side illustrates the polar Asp(a94)... Asn (102) interaction that stabilizes the R (oxy) conformation of human hemoglobin (HbA). This sidechain inter- action underlies the allosteric, structural transition of hemoglobin and helps to maintain its tetramer structure. In the table below the properties of several mutants of hemoglobin involving the a94 position are compared at pH ~ 7.4.

(a) The diagram below on the right-hand side illustrates the polar Asp(a94)... Asn (102) interaction that stabilizes the R (oxy) conformation of human hemoglobin (HbA). This sidechain inter- action underlies the allosteric, structural transition of hemoglobin and helps to maintain its tetramer structure. In the table below the properties of several mutants of hemoglobin involving the a94 position are compared at pH ~ 7.4.

Biochemistry
Biochemistry
9th Edition
ISBN:9781319114671
Author:Lubert Stryer, Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto Jr.
Publisher:Lubert Stryer, Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto Jr.
Chapter1: Biochemistry: An Evolving Science
Section: Chapter Questions
Problem 1P
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1. The human hemoglobin molecule, like all mammalian he- moglobins, is comprised of two a-chains and two ß-chains con- ₂ taining 141 and 146 amino acid residues, respectively. Be- cause the molecule possesses two-fold symmetry, there are a1-a2, B1-B2, and a1-B2 interfaces formed by amino acid sidechains through which structural changes are transmitted underlying ligand binding. The most important of these is the a1-B2 interface that is illustrated in the diagram on the right. All of the sidechain interactions across the a1-B2 interface are hydrophobic except for that between Asp(a94) and Asn- (B102). This is the only polar interaction across the α1-³2 in- terface and it helps to stabilize the oxy- or R-conformation. Its approximate location in the Hb molecule is represented by the red double arrow in the diagram on the right. His FG4 97 Asp G1 (99) Tyr C7 (42) Hb mutant (a) T State (deoxy) 95 The C6 41 (a) The diagram below on the right-hand side illustrates the polar Asp(a94). . . Asn (102) interaction that stabilizes the R (oxy) conformation of human hemoglobin (HbA). This sidechain inter- action underlies the allosteric, structural transition of hemoglobin and helps to maintain its tetramer structure. In the table below the properties of several mutants of hemoglobin involving the a94 position are compared at pH ~ 7.4. 38 POTCDA 44 HbA Hb Bassett Hb Roanne Hb Sunshine Seth oxygenation Amino acid change Asp(a94)Ala Asp(a94) Glu Asp(a94) His Asp(a94)Asn (b) The diagram on the right compares O2-dissoci- ation curves for human hemoglobins characterized by dif- ferent p50 values. If Ko2 represents the equilibrium disso- ciation constant for oxygen binding, e.g., Hb(02)n Hb + nO₂ show the relationship between Ko2 and p50. Assign one of the curves (a, b, . . . , e) that best approxi- mates the Ko2 of each of the mutant hemoglobins in the table above including HbA where Ko2 represents the equi- librium dissociation constant for oxygen binding. If no curve is present for any of the mutant hemogobins, state the rea- son why the mutant is not represented. Indicate on the graph where its p50 would lie. a C terminus His FG4 97 HbA PERCENT SATURATION B₂ OBC 100- JOINT nн 2.8 1.4 2.1 1.1 1.03 0- 0 20 BFG FG Asn G4 (102) Hb Titusville In the style shown on the right for HbA, make a schematic drawing of the potential (a94)... (B102) hydrogen bond- ing relationship for each mutant hemoglobin wherein the dots connect the donor hydrogen (D-H) and acceptor hy- drogen (A) atoms, assuming that it could be formed in the absence of structural distortion of the protein. The change in amino acid residue is represented, e.g., for Hb Bassett as Asp(a94)Ala, meaning that residue Asp at position a94 has been replaced by Ala. 094 WH HỆ CHÍ SWITCH (b) R State (oxy) a/b/c/d/e Asp G1 (94) 01 B₂C terminus The CG 41 p50 (mm Hg) 26 40 9 30 33 38 CDP 44 BID2 PARTIAL PRESSURE OF OXYGEN veins muscle lungs C=O 8 C-CH₂CH NH α₁ 40 60 80 100 120 140 OXYGEN PRESSURE (millimeters of mercury)
Transcribed Image Text:1. The human hemoglobin molecule, like all mammalian he- moglobins, is comprised of two a-chains and two ß-chains con- ₂ taining 141 and 146 amino acid residues, respectively. Be- cause the molecule possesses two-fold symmetry, there are a1-a2, B1-B2, and a1-B2 interfaces formed by amino acid sidechains through which structural changes are transmitted underlying ligand binding. The most important of these is the a1-B2 interface that is illustrated in the diagram on the right. All of the sidechain interactions across the a1-B2 interface are hydrophobic except for that between Asp(a94) and Asn- (B102). This is the only polar interaction across the α1-³2 in- terface and it helps to stabilize the oxy- or R-conformation. Its approximate location in the Hb molecule is represented by the red double arrow in the diagram on the right. His FG4 97 Asp G1 (99) Tyr C7 (42) Hb mutant (a) T State (deoxy) 95 The C6 41 (a) The diagram below on the right-hand side illustrates the polar Asp(a94). . . Asn (102) interaction that stabilizes the R (oxy) conformation of human hemoglobin (HbA). This sidechain inter- action underlies the allosteric, structural transition of hemoglobin and helps to maintain its tetramer structure. In the table below the properties of several mutants of hemoglobin involving the a94 position are compared at pH ~ 7.4. 38 POTCDA 44 HbA Hb Bassett Hb Roanne Hb Sunshine Seth oxygenation Amino acid change Asp(a94)Ala Asp(a94) Glu Asp(a94) His Asp(a94)Asn (b) The diagram on the right compares O2-dissoci- ation curves for human hemoglobins characterized by dif- ferent p50 values. If Ko2 represents the equilibrium disso- ciation constant for oxygen binding, e.g., Hb(02)n Hb + nO₂ show the relationship between Ko2 and p50. Assign one of the curves (a, b, . . . , e) that best approxi- mates the Ko2 of each of the mutant hemoglobins in the table above including HbA where Ko2 represents the equi- librium dissociation constant for oxygen binding. If no curve is present for any of the mutant hemogobins, state the rea- son why the mutant is not represented. Indicate on the graph where its p50 would lie. a C terminus His FG4 97 HbA PERCENT SATURATION B₂ OBC 100- JOINT nн 2.8 1.4 2.1 1.1 1.03 0- 0 20 BFG FG Asn G4 (102) Hb Titusville In the style shown on the right for HbA, make a schematic drawing of the potential (a94)... (B102) hydrogen bond- ing relationship for each mutant hemoglobin wherein the dots connect the donor hydrogen (D-H) and acceptor hy- drogen (A) atoms, assuming that it could be formed in the absence of structural distortion of the protein. The change in amino acid residue is represented, e.g., for Hb Bassett as Asp(a94)Ala, meaning that residue Asp at position a94 has been replaced by Ala. 094 WH HỆ CHÍ SWITCH (b) R State (oxy) a/b/c/d/e Asp G1 (94) 01 B₂C terminus The CG 41 p50 (mm Hg) 26 40 9 30 33 38 CDP 44 BID2 PARTIAL PRESSURE OF OXYGEN veins muscle lungs C=O 8 C-CH₂CH NH α₁ 40 60 80 100 120 140 OXYGEN PRESSURE (millimeters of mercury)
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