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| | <scene name='Sandbox_malka/Hiv_ribbon_sheet/1'>sheet</scene> |
| {{Quote box
| | <scene name='Sandbox_malka/Hiv_ribbon_helix/5'>helix</scene> |
| | quote = <b>Hemoglobin causes Net Diffusion of Oxygen</b><br>Oxygen diffuses freely across oxygen-permeable membranes, following the simple rule of equal pressure. By capturing oxygen, hemoglobin produces a change in the internal pressure of free oxygen, forcing the oxygen influx where it is needed.
| | <scene name='Sandbox_malka/Hiv_ribbon_medicine/1'>drug</scene> |
| | source = [http://highered.mcgraw-hill.com/olcweb/cgi/pluginpop.cgi?it=swf::640::480::/sites/dl/free/0077290828/811360/Hemoglobin_Causes_Net_Diffusion_of_Oxygen.swf::Hemoglobin%20Causes%20Net%20Diffusion%20of%20Oxygen (interactive demo)]
| | <scene name='Sandbox_malka/Hiv_ribbon/3'>active site</scene> |
| | width = 40%
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| ===כיצד מנושמים?=== | | <scene name='Sandbox_malka/Hiv_ribbon_helix/6'>his</scene> |
| בלה בלה בלה.
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| ===Hb, the mighty protein===
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| Hemoglobin (Hb), also spelled haemoglobin, (see on the right a three-dimensional representation of a single molecule) is the protein that carries oxygen from the lungs to the tissues where it's needed. The carbon dioxide produced by the consumption of oxygen. In order to function most efficiently, hemoglobin needs to bind to oxygen tightly in the oxygen-rich atmosphere of the lungs and be able to release oxygen rapidly in the relatively oxygen-poor environment of the tissues. It does this in a most elegant and intricately coordinated way. <u>The story of hemoglobin is the prototype example of the relationship between structure and function of a protein molecule</u>.
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| <applet load='' size='300' frame='true' align='right' caption='' scene='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/1hho_bio/1'/>
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| =====The true colors=====
| | <scene name='Sandbox_malka/Fgf9/2'>active sites in magenta</scene> |
| As you can see, there are <scene name='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/1hho_bio/4'>four</scene> identical gray, red, blue and orange colored, made-of-balls elements. Let's take a closer look to <scene name='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/1hho_bio/6'>one</scene> of them. This is the ''''heme'''' group, the functional unit of hemoglobin.
| | <StructureSection load='2nmz' size='500' side='right' background='none' scene='User:David_Canner/Sandbox_HIV/Opening/2' caption='Structure of HIV Protease'> |
| ''WAIT'': are those the true colors of the heme group? Not really. We are looking at a representation of the real structure, artificially colored following the [[CPK|Corey-Pauling-Koltun]] scheme ( {{Template:ColorKey_Element_C}}
| | [[Image:CannergreyHIV2.png|220px|left]][[Human Immunodeficiency Virus]] (HIV) is the cause of Acquired Immunodeficiency Syndrome (AIDS). HIV directs the synthesis of several polyproteins, which each consist of several tandemly linked proteins. The maturation of the virus to its infectious form requires that these polyproteins be cleaved to their component proteins. <scene name='User:David_Canner/Sandbox_HIV/Opening/2'>HIV-1 protease</scene>, a homodimeric enzyme, is responsible for doing so and is therefore crucial to the virus's infectious capacity. |
| {{Template:ColorKey_Element_H}}
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| {{Template:ColorKey_Element_O}}
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| {{Template:ColorKey_Element_N}}
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| {{Template:ColorKey_Element_S}}
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| {{Template:ColorKey_Element_Fe}} ). ''Remember'': these are artificial representations, using colors, textures, styles and forms chosen with the purpose of helping us to better understand the reality in its rich spacial configuration.
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| This model of the heme group is represented here in a
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| <scene name='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/1hho_hem_styles/1'>spacefill</scene> mode, but we can also draw it as | |
| <scene name='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/1hho_hem_styles/2'>ball and sticks</scene>, maintaining always the same spacial structure and color coded information.
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| =====Capturing Oxygen and other molecules ...===== | | ===Structure of HIV-1 Protease=== |
| The "heart" of the hemoglobin is the <scene name='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/Heme_deoxy/2'>heme</scene> group which is a flat ring molecule containing {{Template:ColorKey_Element_C}}arbon, {{Template:ColorKey_Element_N}}itrogen and {{Template:ColorKey_Element_H}}ydrogen atoms, with a single <font color="#E06633">Fe2+</font> ion at the center. In a heme molecule, the iron is held within the flat plane by four nitrogen ligands from that ring (rotate the structure with your mouse to see the flat plane from its side). <!-- The iron ion makes a fifth bond to a histidine side chain from one of polypeptide chain that forms the heme pocket. --> In the proper conditions, an oxygen molecule gets | | The X-ray structure of HIV-1 protease reveals that it is composed of <scene name='User:David_Canner/Sandbox_HIV/Identical_subunits/1'>two symmetrically related subunits</scene>, each consisting of 99 amino acid residues. The subunits come together in such as way as to <scene name='User:David_Canner/Sandbox_HIV/Tunnel/1'>form a tunnel where they meet</scene>. This tunnel is of critical importance because the active site of the protease is located in its interior. The active site consists of <scene name='User:David_Canner/Sandbox_HIV/Catalytic_triad/3'> two Asp-Thr-Gly conserved sequences</scene>, making it a member of the aspartyl protease family. The two Asp's are <scene name='User:David_Canner/Sandbox_HIV/Catalytic_asp/1'>essential catalytic residues</scene> that activate a water molecule to hydrolytically cleave the polyprotein that binds in the tunnel.<ref>PMID:1799632</ref> You may be wondering how a polyprotein makes its way into the active-site tunnel, as the<scene name='User:David_Canner/Sandbox_HIV/Narrow_tunnel/1'> tunnel appears to be too narrow </scene> to admit it. The key is the two flexible flaps on the top of the tunnel that <scene name='User:David_Canner/Sandbox_HIV/Hiv_tunnel_morph/3'>move to allow proteins </scene>to enter the tunnel. The flaps <scene name='User:David_Canner/Sandbox_HIV/Hiv_tunnel_morph_flaps/2'>undergo a dramatic movement</scene>, shifting from an open to a closed conformation to bind the target in an appropriate conformation for cleavage. |
| <scene name='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/Heme/1'>attached to the Fe</scene> in the heme group. ''OBSERVE'' Are there other changes besides the oxygen being attached to the Fe? | |
| We can watch the capturing of an oxygen molecule in the context of a <scene name='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/Heme/2'>protein single chain</scene> or on a close-up view of the <scene name='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/Heme/1'>isolated Heme</scene> group. {{Template:Button Toggle Animation2}}
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| And now is when things get interesting. The hem group has the chemical and structural capabilities to capture an <scene name='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/O2/1'>oxygen</scene> molecule, which happens to be too close to the general shape of a molecule of <scene name='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/Co/1'>carbon monoxide</scene>, which binds hemoglobin about 240 times faster and better than oxygen, meaning that if both gases are available, hemoglobin will prefer CO over O2. ''THINK'': Can you imagine what will happen if by accident we breathe in a carbon monoxide rich atmosphere?
| | ===Medical Implications=== |
| | There currently is no cure or vaccine against HIV. Researchers, however, have discovered treatments that can halt and even reverse the progression of AIDS, due in large part to our understanding of the structure of HIV-1 protease. <scene name='User:David_Canner/Sandbox_HIV/Saquinavir/4'>Saquinavir</scene> ([[Invirase]]) was the first protease inhibitor approved by the FDA for the treatment of HIV. It inhibits HIV protease by <scene name='User:David_Canner/Sandbox_HIV/Saquinavir_tunnel/1'>binding tightly in the active site tunnel</scene>, preventing the binding of polyproteins. Its chemical structure mimics the tetrahedral intermediate of the hydrolytic reaction, thereby <scene name='User:David_Canner/Sandbox_HIV/Saquinavir_cat/3'>interacting strongly with the catalytic Asp residues</scene>.<ref>PMID:17243183</ref> Saquinavir is essentially an uncleavable ligand, as indicated by the <scene name='User:David_Canner/Sandbox_HIV/Hiv_morph2/9'> similar conformational changes in the protease flaps </scene> on binding saquinavir or a polypeptide . Other drugs used to treat HIV infection that inhibit <scene name='User:David_Canner/Sandbox_HIV/Inhibitor_intro/1'>HIV protease</scene> include <scene name='User:David_Canner/Sandbox_HIV/Indinavir/2'>Indinavir </scene> ([[Crixivan]]), <scene name='User:David_Canner/Sandbox_HIV/Ritonavir/1'>Ritonavir</scene> ([[Norvir]]), and <scene name='User:David_Canner/Sandbox_HIV/Nelfinavir/2'>Nelfinavir</scene> ([[Viracept]]). |
| | __NOEDITSECTION__ |
| | __NOTOC__ |
| | </StructureSection> |
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| =====The whole molecule===== | | ==3D Structures of HIV-1 protease== |
| Let's go back and take a look to the whole picture. Do you remember the four '''heme''' groups in a ribbon-like structure we noticed at the beginning?. This is because the biological active molecule of hemoglobin is a ''tetramer'', this is, a polymer comprising four monomer units: two alpha chains, each with 141 amino acids and two beta chains, each with 146 amino acids. The protein of each of these chains is called ''globin''.
| | # [[Virus protease]] |
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| ===Sickle-cell disease=== | | ==Additional Resources== |
| Sickle hemoglobin differs from normal hemoglobin by a single amino acid: valine (hydrophobic) replaces glutamate (hydrophilic) at position 6 on the surface of the beta chain. This creates an hydrophobic spot. ''THINK'': Why a simple additional hydrophobic spot (actually two spots in the structure ''WHY?''), generated by the change of a single amino acid on a protein with over 500 amino acids becomes so problematic?
| | For additional information, see: [[Human Immunodeficiency Virus]] |
| <applet load='1hbs' size='300' frame='true' align='right' caption='' scene='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/Sickle_one_protein/4'/> | | <br /> |
| On the right, we can see the structure of a deoxygenated hemoglobin, this is, an hemoglobin shortly after releasing the load of oxygen. We can distinguish it's four chains (by it's artificial colors) and the four heme groups with no oxygen attached. This time, the representation is of style ''spacefill'', which is Ok because you know by now that representations are only a different way of drawing a real structure that we can't see.
| | * [http://www.rcsb.org/pdb/static.do?p=education_discussion/educational_resources/hiv-animation.html Structural Biology of HIV], an interactive Flash graphic of the virion with explanations of its components. |
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| Both normal and sickle hemoglobin, when in deoxygenated state, have an
| | ==References== |
| <scene name='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/Dexygenated_hemoglobin/3'>hydrophobic spot</scene> (colored white here)
| | <references/> |
| on the beta chains. Two beta chains = two hydrophobic spots on the dehydrogenated hemoglobin. ''WATCH'': Can you find the spots on the two chains?.
| | <scene name='Sandbox_malka/Hiv_ribbon_helix/3'>helix only</scene> |
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| The <scene name='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/Sickle_hemoglobin/1'>hydrophobic spot</scene> present on Sickle hemoglobin sticks to the hydrophobic spot present on dehydrogenized hemoglobin, causing hemoglobin molecules to
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| <scene name='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/Sickle_hemoglobin_chain/1'>aggregate</scene> into chains forming long fibers. | |
| A <scene name='User:Jaime_Prilusky/How_do_we_get_the_oxygen_we_breathe/Sickle_hemoglobin_chain_close/1'>closer look</scene>
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| shows us that Alanine and Leucine from one molecule attract the Valine from another, chaining the two hemoglobin molecules together.
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| ==Content advisors==
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| This lesson plan was developed together with Dr. Dvora Cohen, Biology Teacher and Dr Mira Kipnis, Chemistry Teacher, both from the Davidson Institute of Science Education, Weizmann Institute of Science. This page include scenes, structures and ideas from [[User:Eric_Martz|Eric Martz]], [[User:Frieda S. Reichsman|Frieda S. Reichsman]] and [[User:Angel_Herraez|Angel Herraez]].
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