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Crystal structure of a monomeric retroviral protease solved by protein folding game players.

ABSTRACT: Following the failure of a wide range of attempts to solve the crystal structure of M-PMV retroviral protease by molecular replacement, we challenged players of the protein folding game Foldit to produce accurate models of the protein. Remarkably, Foldit players were able to generate models of sufficient quality for successful molecular replacement and subsequent structure determination. The refined structure provides new insights for the design of antiretroviral drugs.

SUBMITTER: Khatib F

PROVIDER: S-EPMC3705907 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Crystal structure of a monomeric retroviral protease solved by protein folding game players.

Khatib Firas F DiMaio Frank F Cooper Seth S Kazmierczyk Maciej M Gilski Miroslaw M Krzywda Szymon S Zabranska Helena H Pichova Iva I Thompson James J Popović Zoran Z Jaskolski Mariusz M Baker David D

Nature structural & molecular biology 20110918 10

Following the failure of a wide range of attempts to solve the crystal structure of M-PMV retroviral protease by molecular replacement, we challenged players of the protein folding game Foldit to produce accurate models of the protein. Remarkably, Foldit players were able to generate models of sufficient quality for successful molecular replacement and subsequent structure determination. The refined structure provides new insights for the design of antiretroviral drugs. ...[more]

PMID: 21926992

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Algorithm discovery by protein folding game players.

Project description:Foldit is a multiplayer online game in which players collaborate and compete to create accurate protein structure models. For specific hard problems, Foldit player solutions can in some cases outperform state-of-the-art computational methods. However, very little is known about how collaborative gameplay produces these results and whether Foldit player strategies can be formalized and structured so that they can be used by computers. To determine whether high performing player strategies could be collectively codified, we augmented the Foldit gameplay mechanics with tools for players to encode their folding strategies as "recipes" and to share their recipes with other players, who are able to further modify and redistribute them. Here we describe the rapid social evolution of player-developed folding algorithms that took place in the year following the introduction of these tools. Players developed over 5,400 different recipes, both by creating new algorithms and by modifying and recombining successful recipes developed by other players. The most successful recipes rapidly spread through the Foldit player population, and two of the recipes became particularly dominant. Examination of the algorithms encoded in these two recipes revealed a striking similarity to an unpublished algorithm developed by scientists over the same period. Benchmark calculations show that the new algorithm independently discovered by scientists and by Foldit players outperforms previously published methods. Thus, online scientific game frameworks have the potential not only to solve hard scientific problems, but also to discover and formalize effective new strategies and algorithms.

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Crystal structure of the retroviral protease-like domain of a protozoal DNA damage-inducible 1 protein.

Project description:DNA damage-inducible 1 (Ddi1) is a multidomain protein with one of the domains being retropepsin-like. HIV-1 protease inhibitors were found to reduce opportunistic infections caused by pathogens like Leishmania and Plasmodium, and some of them were shown to inhibit the growth of these parasites. In Leishmania, Ddi1 was identified as a likely target of the inhibitors. We report the crystal structure of the retropepsin-like domain of Ddi1 from Leishmania major as a dimer with clear density for the critical 'flap' region. We have characterized binding with one of the HIV-1 protease inhibitors in solution using bio-layer interferometry and by docking. Further, we have performed molecular dynamics (MD) simulation studies that show that the protein undergoes a conformational change from open to semi-open and closed forms with the closing of the flexible flap over the active site.

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Crystal structure of a defective folding protein.

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Crystal Structure of a Retroviral Polyprotein: Prototype Foamy Virus Protease-Reverse Transcriptase (PR-RT).

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The early years of retroviral protease crystal structures.

Project description:Soon after its discovery, the attempts to develop anti-AIDS therapeutics focused on the retroviral protease (PR)-an enzyme used by lentiviruses to process the precursor polypeptide into mature viral proteins. An urgent need for the three-dimensional structure of PR to guide rational drug design prompted efforts to produce milligram quantities of this enzyme. However, only minute amounts of PR were present in the HIV-1 and HIV-2 viruses, and initial attempts to express this protein in bacteria were not successful. This review describes X-ray crystallographic studies of the retroviral proteases carried out at NCI-Frederick in the late 1980s and early 1990s and puts into perspective the crucial role that the total protein chemical synthesis played in unraveling the structure, mechanism of action, and inhibition of HIV-1 PR. Notably, the first fully correct structure of HIV-1 PR and the first cocrystal structure of its complex with an inhibitor (a substrate-derived, reduced isostere hexapeptide MVT-101) were determined using chemically synthesized protein. Most importantly, these sets of coordinates were made freely available to the research community and were used worldwide to solve X-ray structures of HIV-1 PR complexes with an array of inhibitors and set in motion a variety of theoretical studies. Publication of the structure of chemically synthesized HIV-1 PR complexed with MVT-101 preceded only by six years the approval of the first PR inhibitor as an anti-AIDS drug.

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Minds at Play: Using an Online Protein Folding Game, FoldIt, To Support Student Learning about Protein Folding, Structure, and the Scientific Process.

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Crystal structure of monomeric Amuc_1100 from Akkermansia muciniphila.

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Human core duplicon gene families: game changers or game players?

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