Aashish Manglik

What's that smell? Readers share the scents that remind them of L.A. From wafting tar pits and smells of the beach to native plants and a chocolate factory, our readers smelled Los Angeles and told us about it.

FRI at 10AM:

@latimes.com journalist Maxwell Williams and UCSF pharmaceutical chemistry professor @amanglik.bsky.social join to talk about the unique scents that surround us in the Golden State.

❓What smell says California to you? Sequoia trees? Ojai tangerines? Ocean spray?

Phenotypic pleiotropy of missense variants in human B cell-confinement receptor P2RY8 Missense variants can have pleiotropic effects on protein function and predicting these effects can be difficult. We performed near-saturation deep mutational scanning of P2RY8, a G-protein-coupled re...

1/n: 2nd preprint this week: www.biorxiv.org/content/10.1.... We functionalized a G(13)PCR P2RY8 that keeps germinal center (GC) B cells confined. Taylor LaFlam performed saturation mutagenesis, Aashish Manglik's lab solved the structure, and collaboration with Cyster lab validated variant effects.

We have deposited the following mice (all B6/J backcrossed) to @mmrrc.bsky.social
Adgrf5-EGFP-CT-IRES-CRE
GPR123- EGFP-CT-IRES-CRE
GPR124- EGFP-CT-IRES-CRE
GPR125- EGFP-CT-IRES-CRE
Gpr133-EGFP-CT-IRES-CRE
GPR156-IRES-Cre
GPR156-mGL-IRES-Cre
GPR75-IRES-Cre

Wow what a great resource - thanks Brian!

Please check out our recent work led by brilliant student @matthewkhoward.bsky.social jointly mentored with @willowcoyote.bsky.social. Willow and I are recruiting joint postdocs - contact us!

Tune in for @matthewkhoward.bsky.social to give a talk tomorrow!

Brilliant student from my and @amanglik.bsky.social’s lab working on transformational DMS approaches for gpcrs. Also right on the heels of his first paper from our labs!!!

We think the consensus approach will allow the field to better model the OR family, especially if combined with the latest approaches in small molecule-protein complex prediction by methods like AF3. We are actively pursuing these now!

These structures, combined with mutagenesis studies in Hiro's group and extensive simulation work by Ning Ma and Vaidehi Nagarajan highlighted several unique properties of odorant recognition. The most baffling is that the receptor pockets are large, and odorants are quite flexible in the pocket.

So far, we had only seen how fish-like" odorant receptors recognize their odorants, which are typically water soluble. We really wanted to examine the much larger family of receptors that allow us to sense volatile odorants. Using the consensus strategy, we obtained several more structures.

Luckily Christian Billesboelle solved a structure of a native human OR, OR51E2, which we reported last year - www.nature.com/articles/s41.... This provided clear context for the consensus structure, and highlighted that the consensus structures are great mimics of the native structures.

Working with @scicadm.bsky.social, I was able to show that these constructs were highly tractable - students in my lab much more adept at cryoEM than I am helped me solve a structure of the first such receptor, OR51. We got this result, but were unsure what to make of it.

This started with a cold email to Hiro Matsunami because I was excited by their brilliant paper in PNAS (www.pnas.org/doi/10.1073/...) where they demonstrated that designing "consensus" receptors overcame the central challenge in expression that plagues the field.

First post on bsky to highlight our latest work on smell receptors (www.nature.com/articles/s41...). Odorant receptors are notoriously challenging to work with - we used a classic strategy from protein engineering to get a peek into how these receptors recognize such a diversity of smells.