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<meta name="author" content="Michael J. Harms">
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<h2>Allostery</h2>
<h4>2017-10-27</h4>
<br/>
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<section>
<small>You measure MM curves for a variety of enzymes (solid curves). You add molecule $A$ to each solution and remeasure its MM curve (dashed line). <span style="color:red">For each curve: What changed ($K_{M}$ or $V_{max}$)? Is this a competitive or noncompetitive inhibitor?</small>
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<img class="img-responsive" src="presentation-data/14/img/km_competitive.png"/>
<small class="fragment" style="color:blue">$K_{M}$, competitive</small>
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<img class="img-responsive" src="presentation-data/14/img/noncompetitive.png"/>
<small class="fragment" style="color:blue">$V_{max}$, noncompetitive</small>
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<img class="img-responsive" src="presentation-data/14/img/allosteric-activator.png"/>
<small class="fragment" style="color:blue">$V_{max}$, activator</small>
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<p>Competitive inhibitor</p>
<ul>
<li>Inhibitor competes with substrate for same site</li>
<li>This raises $K_{M}$: lower apparent affinity for substrate because it has to compete</li>
<li>No effect on $V_{max}$. If you add enough substrate, you swamp out competitor</li>
<li>Inhibitor is chemically similar to the substrate</li>
<li>Example: Ethanol competes with methanol for alcohol dehydrogenase, lowering the rate of formaldehyde production.</li>
</ul>
</section>
<section>
<p>Noncompetitive inhibitor</p>
<ul>
<li>Binds distant from the active site, altering active site to turn off activity</li>
<li>This leads to a drop in $V_{max}$. (lower $[E]_{T}$: Less of the enzyme is in the active form.)</li>
<li>No effect on $K_{M}$. What active enzyme is around has exact same affinity for substrate</li>
<li>The inhibitor need not have any chemical similarity to the substrate</li>
</ul>
</section>
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<p>Example noncompetitive inhibitor</p>
<video class="video-responsive" data-autoplay mute loop height="90%" width="90%"/>
<source data-src="presentation-data/13/video/hcv-polymerase-inhibitor.mp4" />
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<section>
<h4>Conceptual goals</h4>
<ul>
<li class="fragment">Understand that binding at one site in a protein can alter activity at another site</li>
<li class="fragment">This "allostery" arises because the "allosteric effector" interacts with one conformation, but not the other.</li>
<li class="fragment">Understand how this applies to hemoglobin (BPG).</li>
</ul>
<h4>Skill goals</h4>
<ul>
<li class="fragment">Determine how binding at on site affects activity at the other</li>
<li class="fragment">Predict the effects of adding allosteric effectors to a system of equilibria.</li>
</ul>
</section>
<section>
<p>Hemoglobin transports $O_{2}$ from the lungs to tissues</p>
<img src="presentation-data/14/img/red-blood-cell.jpg" height="60%" width="60%"/>
<br/>
<small><a href="https://stephaniefuturedoc.files.wordpress.com/2012/07/red-blood-cell.jpg">stephaniefuturedoc</a></small>
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<p>Hemoglobin is a tetramer four proteins</p>
<img src="presentation-data/14/img/hemoglobin.png" height="90%" width="90%" /><br/>
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<p>Each subunit binds $O_{2}$ using a "heme" group with a bound $Fe(II)$ and a proximal His</p>
<img src="presentation-data/14/img/myoglobin.jpg" /><br/>
<small>Credit: <a href="http://jeb.biologists.org/content/207/20/3441">Ordway & Garry (2004) JEB 207:3441-3446</a></small>
</section>
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<video class="video-responsive" data-autoplay mute controls height="90%" width="90%"/>
<source data-src="presentation-data/14/video/hemoglobin1.mp4" />
<source data-src="presentation-data/14/video/hemoglobin1.mov" />
</video>
<small>Credit: <a href="http://biochem.web.utah.edu/iwasa/projects/hemoglobin.html">Janet Iwasa (Utah)</a></small>
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<source data-src="presentation-data/14/video/hemoglobin-dpg.mp4" />
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<small>Credit: <a href="http://biochem.web.utah.edu/iwasa/projects/hemoglobin.html">Janet Iwasa (Utah)</a></small>
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<video class="video-responsive" data-autoplay mute loop height="90%" width="90%"/>
<source data-src="presentation-data/14/video/hemoglobin-t-to-r.mp4" />
<source data-src="presentation-data/14/video/hemoglobin-t-to-r.mov" />
</video>
<small>Credit: <a href="http://biochem.web.utah.edu/iwasa/projects/hemoglobin.html">Janet Iwasa (Utah)</a></small>
</section>
<section>
<p></p>
</section>
<section>
<p>This is through <em>linked equilibria</em></p>
<p>$E_{active} + I \rightleftarrows E_{inactive} + I \rightleftarrows E_{inactive} \cdot I$</p>
<p class="fragment">$[E]_{active} = [E]_{T}\theta_{active}$</p>
<p class="fragment">$\theta_{active} = \frac{[E_{active}]}{[E_{active}] + [E_{inactive}] + [E_{inactive}\cdot I]}$</p>
</section>
<section>
<p>What are the ingredients you would need for allostery?</p>
</section>
<section>
<p>Ingredients:</p>
<ul>
<li>Two different binding sites recognizing different things</li>
<li>Equilibrium between two (or more) protein shapes</li>
<li>Different "activities" (functions, properties, etc.) of each shape</li>
<li>Binding to one shape, but not the others</li>
</ul>
</section>
<section>
<p>Summary</p>
<p>Allostery is when binding at one site in a protein alters activity at another site</p>
<ul>
<li>Two different binding sites recognizing different things</li>
<li>Equilibrium between two (or more) protein shapes</li>
<li>Different "activities" (functions, properties, etc.) of each shape</li>
<li>Binding to one shape, but not the others</li>
</ul>
<p>Noncompetitive inhibitors</p>
<p>BPG allosterically regulates $O_{2}$ binding in hemoglobin</p>
</section>
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