Lecture 13 - Friday Lecture 13 Announcements 1 Quiz 3...

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Friday, September 22, 2006, Lecture 13 Announcements: 1. Quiz 3 results: 3a 27.1 3b 27.0 3c 26.4 2. Meet today at 1:25PM in Comstock B106: “Applying to medical school, the role of the HCEC, and letters of recommendation" 3. The Rasmol file fix seems to work. If you use a Windows computer, see the Blackboard announcements to get the files. 4. Meeting today, 5PM in Rockefeller 105: SOL, the CU Science Organization of Latinos. Wednesday's lecture: Ion pairs stabilize the structure of deoxy-Hb. In addition, Hb from all species have additional ion pairs to a small, negatively charged molecule. In mammals, this is 2,3-bisphosphoglycerate (BPG). Today: p. 91 Why does oxygen binding disrupt distant ion pairs? Maybe we can answer that question by asking what is the exact connection of the heme to subunit contacts? The text explanation (from Max Perutz, Nobel Prize laureate for the X-ray diffraction structure of Hb) starts from the fact that the proximal His is bound to Fe 2+ . When O 2 binds, the Fe 2+ is pulled slightly toward the O 2 , about 0.5Å, dragging the His and the F helix (of which this His is a part), with it. See the text figure 5-11. There is some debate over whether this simple explanation is the whole story. We can also turn to a general picture of why IV structure can lead to “modified action” (allostery and cooperativity): 1. Think of Mb single chain as a “device” that evolved to bind oxygen. It does a great job of binding oxygen. 2. When this single polypeptide chain binds oxygen, small changes occur in the 3-d structure. For Mb, these small changes have no influence - they pose no constraint. The small changes in structure occur throughout the Mb, but there is no “resistance” to these small changes.
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Now, what happens if you bring four of these “O 2 -binding devices” together and stick them tightly to each other? The four devices come together in a quaternary structure that optimizes the subunit contacts . In the case of Hb, we notice especially the 8 ion pairs. This IV structure, with strong, optimized subunit contacts, is called the tight, or T state. Any change in this state is strongly resisted by numerous interactions. 3. Now the numerous small 3-d changes as a result of oxygen binding are resisted by the contacts between the chains. The small changes occur throughout the 3d structure, but at the subunit interfaces any such small changes are resisted by the strong binding. 4. Therefore, in deoxy Hb the oxygen binding is not optimized , because the subunit contacts have been optimized . So binding oxygen is more difficult. After oxygens have bound and the ion pairs have broken, this new IV structure has much less resistance to more oxygen binding. We call this the relaxed, or R state of Hb. These 4 points are a very general explanation for cooperative O 2 binding, without claiming to know the precise link between the O 2 and all the residues in- between the O 2 and the subunit interfaces.
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