Flaps Morph for HIV Protease: Difference between revisions
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The proteolytic active site of HIV protease is [[Immunodeficiency virus protease|covered by two "flaps"]]. It is believed that these flaps must open to enable substrate polyprotein to enter the active site. Drugs that inhibit HIV protease tend to "lock" the flaps closed<ref>PMID:22291339</ref>. Mutations in HIV protease that confer resistance to inhibitor drugs often involve changes to the flaps<ref name="wide-open" />. The ''active site expansion'' hypothesis states that mutations responsible for multi-drug resistance expand the active site cavity, thereby reducing drug affinity<ref name="wide-open" />. | The proteolytic active site of HIV protease is [[Immunodeficiency virus protease|covered by two "flaps"]]. It is believed that these flaps must open to enable substrate polyprotein to enter the active site. Drugs that inhibit HIV protease tend to "lock" the flaps closed<ref>PMID:22291339</ref>. Mutations in HIV protease that confer resistance to inhibitor drugs often involve changes to the flaps<ref name="wide-open" />. The ''active site expansion'' hypothesis states that mutations responsible for multi-drug resistance expand the active site cavity, thereby reducing drug affinity<ref name="wide-open" />. | ||
There are [[Immunodeficiency virus protease 3D structures|hundreds of HIV protease crystal structures]]. When crystallized with bound inhibitor, the flaps have always been closed<ref name="processes" />. Inhibitor-free crystal structures have been classified into '''closed, semi-open,''' and '''wide open'''<ref name="processes" />. As of 2017, no crystal structure has captured a '''fully open''' conformation, defined as a distance of >13 Å between isoleucine 50's at the tips of the flaps<ref name="wide-open" />. | There are [[Immunodeficiency virus protease 3D structures|hundreds of HIV protease crystal structures]]. When crystallized with bound inhibitor, the flaps have always been closed<ref name="processes">Yu, Y. ''et al.'', Structural insights into HIV-1 protease flap opening processes and key intermediates. 2017 RSC Advances, '''7''':45121-8. '''NOT IN PUBMED.''' [https://pubs.rsc.org/en/content/articlehtml/2017/ra/c7ra09691g OPEN ACCESS]. DOI: [https://doi.org/10.1039/C7RA09691G 10.1039/C7RA09691G].</ref>. Inhibitor-free crystal structures have been classified into '''closed, semi-open,''' and '''wide open'''<ref name="processes" />. As of 2017, no crystal structure has captured a '''fully open''' conformation, defined as a distance of >13 Å between isoleucine 50's at the tips of the flaps<ref name="wide-open" />. | ||
In the case of mutant [[1tw7]], about 100 water molecules 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 reside in the active site, forming a hydrogen-bonded scaffold holding the flaps open<ref name="wide-open" />. | ||
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*Course-grained<ref>PMID:17029846 </ref> | *Course-grained<ref>PMID:17029846 </ref> | ||
<table class="wikitable" style="text-align:center;"> | <table class="wikitable" style="text-align:center;"> | ||
Revision as of 02:46, 23 February 2020
The genome of HIV codes for synthesis of a polyprotein (UniProt P04585 (POL_HV1H2)) that requires cutting by HIV protease in order to be separated into individual mature proteins required for virus maturation[1]. Drugs that inhibit HIV protease prevent the virus from replicating, and are crucial components of anti-HIV therapies.
The proteolytic active site of HIV protease is covered by two "flaps". It is believed that these flaps must open to enable substrate polyprotein to enter the active site. Drugs that inhibit HIV protease tend to "lock" the flaps closed[2]. Mutations in HIV protease that confer resistance to inhibitor drugs often involve changes to the flaps[1]. The active site expansion hypothesis states that mutations responsible for multi-drug resistance expand the active site cavity, thereby reducing drug affinity[1].
There are hundreds of HIV protease crystal structures. When crystallized with bound inhibitor, the flaps have always been closed[3]. Inhibitor-free crystal structures have been classified into closed, semi-open, and wide open[3]. As of 2017, no crystal structure has captured a fully open conformation, defined as a distance of >13 Å between isoleucine 50's at the tips of the flaps[1].
In the case of mutant 1tw7, about 100 water molecules reside in the active site, forming a hydrogen-bonded scaffold holding the flaps open[1].
- Course-grained[4]
|
Wide-Open Drug-Free HIV Protease Crystal Structures[3] |
||||||
|
PDB ID |
Year |
Resolution; Rfree* |
Asymm. Unit |
Ile50 dist. |
Mutations; Comments |
Wild Type |
|
2005 |
1.3 Å; WTA* |
2 chains |
12.25 Å |
I10L, N25D, V36M, L46M, V54I, V62I, P63L, V71A, A82V, V84I, M90L | ||
|
2007 |
1.4 Å; BTA* |
1 chain |
12.2 Å |
K7Q | ||
|
2008 |
1.2 Å; A* |
1 chain |
12.19 Å |
K7Q, I33L, R41K, I63L | ||
|
Other HIV Protease Crystal Structures With Separated Flaps |
||||||
|
2014 |
1.66 Å; A* |
1 chain |
13.2 Å |
D25N; Inhibitor is between flaps | ||
|
2011 |
2.25 Å; U* |
1 chain |
11.9 Å |
V10I, N25D, E35D, V36I, L46M, A82T; Structure unreliable according to Rfree. | ||
- Rfree is categorized by FirstGlance in Jmol as A (Average), BTA (Better Than Average), U (Unreliable), WTA (Worse Than Average) at the corresponding resolution.
- I did not finish examining hits via google for 'hiv protease flaps animation'
- Immunodeficiency virus protease includes morphs of flap movements and saquinavir binding. (HIV-1 protease redirects here.)
- Immunodeficiency virus protease 3D structures lists hundreds of crystal structures of HIV proteases.
- HIV Protease Inhibitor Resistance Profile
- Molecular Playground/HIV Protease Inhibitor includes an animated simulation of the protease inhibitor Ritonavir binding to the protease.
- Group:SMART:HIV-1 Subtype C Protease
- Protease
- Human Immunodeficiency Virus
- Journal:Acta_Cryst_D:S2059798319011355 Comparison of a retroviral protease crystallized as a monomer and a dimer.
- User:Tsung-Yi_Lin/Sandbox
- User:Dan_Huettner/Sandbox_1, User:Dan_Huettner/Sandbox_3
- User:David Canner/Sandbox HIV
- Sandbox 645
- Sandbox_Reserved_712
- Sandbox Reserved 955
- User:Nicole Maille/Sandbox 1
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Martin P, Vickrey JF, Proteasa G, Jimenez YL, Wawrzak Z, Winters MA, Merigan TC, Kovari LC. "Wide-open" 1.3 A structure of a multidrug-resistant HIV-1 protease as a drug target. Structure. 2005 Dec;13(12):1887-95. PMID:16338417 doi:10.1016/j.str.2005.11.005
- ↑ Heal JW, Jimenez-Roldan JE, Wells SA, Freedman RB, Romer RA. Inhibition of HIV-1 protease: the rigidity perspective. Bioinformatics. 2012 Feb 1;28(3):350-7. doi: 10.1093/bioinformatics/btr683. PMID:22291339 doi:http://dx.doi.org/10.1093/bioinformatics/btr683
- ↑ 3.0 3.1 3.2 Yu, Y. et al., Structural insights into HIV-1 protease flap opening processes and key intermediates. 2017 RSC Advances, 7:45121-8. NOT IN PUBMED. OPEN ACCESS. DOI: 10.1039/C7RA09691G.
- ↑ Tozzini V, Trylska J, Chang CE, McCammon JA. Flap opening dynamics in HIV-1 protease explored with a coarse-grained model. J Struct Biol. 2007 Mar;157(3):606-15. doi: 10.1016/j.jsb.2006.08.005. Epub 2006 , Aug 23. PMID:17029846 doi:http://dx.doi.org/10.1016/j.jsb.2006.08.005