Flaps Morph for HIV Protease: Difference between revisions
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<StructureSection load='' size='350' side='right' caption='HIV protease: morph of flaps opening/closing ([[1hxw]] ↔ [[1tw7]]).' scene='83/836583/Morph/ | <StructureSection load='' size='350' side='right' caption='HIV protease: morph of flaps opening/closing ([[1hxw]] ↔ [[1tw7]]).' scene='83/836583/Morph/8'> | ||
The genome of HIV codes for synthesis of a polyprotein (UniProt [https://www.uniprot.org/uniprot/P04585 P04585 (POL_HV1H2)]) that requires cutting by HIV protease in order to be separated into individual mature proteins required for virus maturation<ref name="wide-open">PMID:16338417</ref>. Drugs that inhibit HIV protease prevent the virus from replicating, and are [[Molecular Playground/HIV Protease Inhibitor|crucial components of anti-HIV therapies]]. | The genome of HIV codes for synthesis of a polyprotein (UniProt [https://www.uniprot.org/uniprot/P04585 P04585 (POL_HV1H2)]) that requires cutting by HIV protease in order to be separated into individual mature proteins required for virus maturation<ref name="wide-open">PMID:16338417</ref>. Drugs that inhibit HIV protease prevent the virus from replicating, and are [[Molecular Playground/HIV Protease Inhibitor|crucial components of anti-HIV therapies]]. | ||
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<center>{{Template:Green_links_zoom}}</center> | <center>{{Template:Green_links_zoom}}</center> | ||
Here is shown a morph between a closed HIV protease and a "wide open" protease (<scene name='83/836583/Morph/ | Here is shown a morph between a closed HIV protease ([[1hxw]]) and a "wide open" protease ([[1tw7]], <scene name='83/836583/Morph/8'>restore initial scene</scene>). The catalytic <font color="red">'''Asp 25's are red'''</font>. (Note that "wide open" is not "fully open" -- see above.) | ||
<center>{{Template:Button_Toggle_Animation2}}</center> | <center>{{Template:Button_Toggle_Animation2}}</center> | ||
''Click the Toggle Animation Button above to start these animations if needed.'' | ''Click the Toggle Animation Button above to '''start''' these animations if needed.'' | ||
* <scene name='83/836583/Morph/ | * <scene name='83/836583/Morph/11'>Morph of ribbon/cartoon with</scene> <font color="magenta">'''flap glycines in magenta'''</font> (Gly 40, 48, 49, 51, 52). | ||
* <scene name='83/836583/Morph/ | * <scene name='83/836583/Morph/12'>Morph of ribbon/cartoon with flaps highlighted</scene> in <font color="orange">'''orange'''</font>. (Flaps: residues 42-58.) | ||
* <scene name='83/836583/Morph/ | * <scene name='83/836583/Morph/13'>Morph of spacefilling rendition</scene> with flaps highlighted in <font color="orange">'''orange'''</font>. | ||
In the case of mutant [[1tw7]], about 100 water molecules (not shown) reside in the active site, forming a hydrogen-bonded scaffold holding the flaps open<ref name="wide-open" />. | In the case of mutant [[1tw7]], about 100 water molecules (not shown) reside in the active site, forming a hydrogen-bonded scaffold holding the flaps open<ref name="wide-open" />. | ||
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==Relevant Resources== | ==Relevant Resources== | ||
===YouTube=== | ===YouTube=== | ||
*[https://www.youtube.com/watch?v=fDFNGo9UfBI Coarse-grained | *[https://www.youtube.com/watch?v=dDo_s6a3wcM HIV protease action]: Excellent half-minute video from the [[PDB]] simulating polyprotein entering protease active site between the flaps, polyprotein hydrolysis, and binding of saquinavir locking the protease closed, inactivating it. | ||
*[https://www.youtube.com/watch?v=9XfJ1NGlUxc Mechanism and Inhibition of Aspartyl Protease Enzymes] (which include HIV protease) explained by [https://www.chemistry.gatech.edu/people/evans/michael Michael Evans (Georgia Tech)]. Excellent detailed explanation of the catalytic mechanism and design of inhibitors. | |||
*[https://www.youtube.com/watch?v=lcLbmuPH4VM Wide-opening of the HIV-1 protease active site]. 50 ns all-atom molecular dynamics simulation of | |||
*[https://www.youtube.com/watch?v=fDFNGo9UfBI Coarse-grained Brownian dynamics simulation]. 2 ns simulation shows flaps opening and substrate binding. | |||
===Other External Resources=== | |||
*[https://pdb101.rcsb.org/motm/6 HIV-1 Protease] in the [[PDB|RCSB PDB]] Molecule of the Month. | |||
*[https://en.wikipedia.org/wiki/HIV-1_protease HIV-1 Protease] in Wikipedia. Includes a link to this page. | |||
*[https://en.wikipedia.org/wiki/Discovery_and_development_of_HIV-protease_inhibitors Discovery and development of HIV-protease inhibitors] in Wikipedia. | |||
===Well-Developed, in Proteopedia=== | ===Well-Developed, in Proteopedia=== | ||
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Year | Year | ||
</td><td> | </td><td> | ||
Resolution; Rfree* | [[Resolution]]; [[Rfree|R<sub>free</sub>]]* | ||
</td><td> | </td><td> | ||
Asymm. Unit | [[Asymmetric unit|Asymm. Unit]] | ||
</td><td> | </td><td> | ||
Ile50 dist.† | Ile50 dist.† | ||
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12.25 Å | 12.25 Å | ||
</td><td> | </td><td> | ||
L10I, D25N, M36V, M46L, I54V, I62V, L63P, A71V, V82A, I84V, L90M | |||
</td><td> | </td><td> | ||
[[3phv]] | [[3phv]] | ||
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12.2 Å | 12.2 Å | ||
</td><td> | </td><td> | ||
Q7K | |||
</td><td> | </td><td> | ||
</td> | </td> | ||
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12.19 Å | 12.19 Å | ||
</td><td> | </td><td> | ||
Q7K, L33I, K41R, L63I | |||
</td><td> | </td><td> | ||
</td> | </td> | ||
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11.9 Å | 11.9 Å | ||
</td><td> | </td><td> | ||
V10I, | V10I, D25N, D35E, I36V, M46L, T82A; Structure unreliable according to Rfree. | ||
</td><td> | </td><td> | ||
</td></tr></table> | </td></tr></table> | ||
<nowiki>*</nowiki>Rfree is categorized by [[FirstGlance in Jmol]] as A (Average), BTA (Better Than Average), U (Unreliable), WTA (Worse Than Average) at the corresponding resolution. | <nowiki>*</nowiki>[[Rfree|R<sub>free</sub>]] is categorized by [[FirstGlance in Jmol]] as A (Average), BTA (Better Than Average), U (Unreliable), WTA (Worse Than Average) at the corresponding resolution. | ||
<br> | <br> | ||
† Distance between the Ile50 alpha carbons in each chain. These are near the tips of the flaps, and this distance is commonly used in the literature to measure the openness of the flaps. | † Distance between the Ile50 alpha carbons in each chain. These are near the tips of the flaps, and this distance is commonly used in the literature to measure the openness of the flaps. | ||
==References== | ==References== | ||
<references /> | <references /> | ||