Flaps Morph for HIV Protease

From Proteopedia

Relevant Resources

YouTube

• 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.
• Mechanism and Inhibition of Aspartyl Protease Enzymes (which include HIV protease) explained by Michael Evans (Georgia Tech). Excellent detailed explanation of the catalytic mechanism and design of inhibitors.
• Wide-opening of the HIV-1 protease active site. 50 ns all-atom molecular dynamics simulation of
• Coarse-grained Brownian dynamics simulation. 2 ns simulation shows flaps opening and substrate binding.

Other External Resources

• HIV-1 Protease in the RCSB PDB Molecule of the Month.
• HIV-1 Protease in Wikipedia. Includes a link to this page.
• Discovery and development of HIV-protease inhibitors in Wikipedia.

Well-Developed, in Proteopedia

• 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.

Sandboxes in Proteopedia

• 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

Flaps in Other Proteins

These were found by searching for "flaps" in Proteopedia.

• Sandbox 215: Omega flaps in cholesterol ester transfer protein.
• Fatty acid amide hydrolase, Sandbox_Reserved_921, Sandbox_Reserved_922

Methods

1hxw, containing the inhibitor Ritonavir, was selected in part because it is more closed than an early, unliganded wild type structure: Ile50 to Gly27 is 11.6 Å in 1hxw, vs. 16.9 Å in 3phv. (The only mutation in 1hxw is S37N.) 1tw7, with "wide open" flaps, was selected in part because its asymmetric unit contains two chains. It has many drug-resistance mutations (see table below).

The morph was generated by Proteopedia's PyMOL Morpher. 1tw7 was pre-aligned with 1hxw, aligning only residues 1-35. Alignment was done in the Jmol Java Application with the following script:

load =1hxw # "=" means load from RCSB PDB.
load append =1tw7 # add this model rather than replacing the previously loaded model.
frame all # display both models.
background white
trace only
color polymer
delay 2.0
compare {2.1} {1.1} subset {*.ca} atoms {1-35} {1-35} rotate translate 2.0 # moves model 2 to align with model 1
select 2.1 # "2.1" is the second model loaded
write 1tw7-aligned-to-1hxw.pdb

*R_free is categorized by FirstGlance in Jmol as A (Average), BTA (Better Than Average), U (Unreliable), WTA (Worse Than Average) at the corresponding resolution.
† 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

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
2. ↑ 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. ↑ ^{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.