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Toni
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Message 52212 - Posted: 9 Jul 2019 | 10:08:50 UTC
Last modified: 14 Jul 2019 | 10:47:54 UTC

Dears,

we added a badge for a (not-so-recent-any-more) paper Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity. The abstract is here and the text is open-access.

It is interesting because it provides evidence about the kinetics (i.e., transient conformational changes) incurred by the µ-opioid receptor (MOR) upon binding to drugs. MOR is part of the large and important GPCR protein family, which is targeted by approx ~30% of the current drugs.

Abhijeet Kapoor, Gerard Martinez-Rosell, Davide Provasi, Gianni de Fabritiis & Marta Filizola
Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity
Scientific Reports volume 7, Article number: 11255 (2017)


While the therapeutic effect of opioids analgesics is mainly attributed to µ-opioid receptor (MOR) activation leading to G protein signaling, their side effects have mostly been linked to β-arrestin signaling. To shed light on the dynamic and kinetic elements underlying MOR functional selectivity, we carried out close to half millisecond high-throughput molecular dynamics simulations of MOR bound to a classical opioid drug (morphine) or a potent G protein-biased agonist (TRV-130). Statistical analyses of Markov state models built using this large simulation dataset combined with information theory enabled, for the first time: a) Identification of four distinct metastable regions along the activation pathway, b) Kinetic evidence of a different dynamic behavior of the receptor bound to a classical or G protein-biased opioid agonist, c) Identification of kinetically distinct conformational states to be used for the rational design of functionally selective ligands that may eventually be developed into improved drugs; d) Characterization of multiple activation/deactivation pathways of MOR, and e) Suggestion from calculated transition timescales that MOR conformational changes are not the rate-limiting step in receptor activation.

[CSF] Thomas H.V. Dupont
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Message 52243 - Posted: 13 Jul 2019 | 8:06:29 UTC

Thanks for this unexpected badge! And thanks for the heads-up, Toni!
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[CSF] Thomas H.V. Dupont
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Toni
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Message 52259 - Posted: 14 Jul 2019 | 10:50:15 UTC - in response to Message 52243.

Here's the top-20 list

rank userid credit

1 358176 849294000
2 93201 551227600
3 14310 474189150
4 101936 362332900
5 100499 347974625
6 126468 296886825
7 25378 293348100
8 68549 280535475
9 9991 241162075
10 36684 200853150
11 28899 169370700
12 69336 156029300
13 116931 153182050
14 109388 148951850
15 125700 133169950
16 31053 133007250
17 59165 131014175
18 62432 118038850
19 73475 116859275
20 97126 108358200

[CSF] Thomas H.V. Dupont
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Message 52277 - Posted: 16 Jul 2019 | 6:06:17 UTC

Thanks Toni!
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[CSF] Thomas H.V. Dupont
Founder of the team CRUNCHERS SANS FRONTIERES
www.crunchersansfrontieres.org

Profile Retvari Zoltan
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Message 52281 - Posted: 16 Jul 2019 | 11:18:58 UTC - in response to Message 52259.

Here's the top-20 list

rank | ----credits---- | user
_1__| 849,294,000 | Syracuse University
_2__| 551,227,600 | RaymondFO*
_3__| 474,189,150 | Retvari Zoltan
_4__| 362,332,900 | Rion Family
_5__| 347,974,625 | jjch
_6__| 296,886,825 | Gunde
_7__| 293,348,100 | Stoneageman
_8__| 280,535,475 | AND
_9__| 241,162,075 | Beyond
10__| 200,853,150 | Grzegorz Roman Granowski
11__| 169,370,700 | Bob Deller
12__| 156,029,300 | neilp62
13__| 153,182,050 | Nicolas CAZIN
14__| 148,951,850 | caffeineyellow5
15__| 133,169,950 | Erich56
16__| 133,007,250 | Thomas M. Taylor
17__| 131,014,175 | Bikermatt
18__| 118,038,850 | om
19__| 116,859,275 | Viktor Svantner
20__| 108,358,200 | captainjack

I've made the toplist human readable.
I hope I've corrected all typos.

[CSF] Thomas H.V. Dupont
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Message 52288 - Posted: 17 Jul 2019 | 5:08:04 UTC

Thanks Zoltan and congrats for your 3rd place!
____________
[CSF] Thomas H.V. Dupont
Founder of the team CRUNCHERS SANS FRONTIERES
www.crunchersansfrontieres.org

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Message boards : News : New badge, new(ish) paper