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Matt Howard

@matthewkhoward.bsky.social

150 followers 250 following 23 posts

Doing science @UCSF in the Coyote-Maestas and Manglik Labs. Former Jackrel Lab @WUSTL www.matthewkhoward.com

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Matt Howard @matthewkhoward.bsky.social · Jan 6

Happy New Year! (and first post here 😀) Excited to share the final version of our work where we combine deep mutational scanning, cryo-EM, and molecular dynamics to further resolve the mechanisms of pH sensing in GPCRs.

🧵(1/n)

www.cell.com/cell/fulltex...

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Matt Howard @matthewkhoward.bsky.social · Jul 21

Congratulations!! 🥳

Matt Howard @matthewkhoward.bsky.social · Jun 30

Check out Jerome's paper! As we push the boundaries of DMS, it is critical that we develop robust ways to score variant effects--and he is doing just that. Excited to put this to use in our upcoming GPCR-DMS endeavors :)

Jerome @jeromics.bsky.social · Jun 30

Check out our new preprint on Lilace, a statistical tool for scoring FACS-based deep mutational scanning experiments! Lilace directly models the shift between variant fluorescence distributions and provides score uncertainty estimates to better assess reliability and reproducibility. (1/3)

Accurate variant effect estimation in FACS-based deep mutational scanning data with Lilace

Deep mutational scanning (DMS) experiments interrogate the effect of genetic variants on protein function, often using fluorescence-activated cell sorting (FACS) to quantitatively measure molecular ph...

www.biorxiv.org

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Reposted by Matt Howard

Ishan Deshpande @ishand.bsky.social · Mar 26

We are hiring a #postdoc in the Deshpande lab! Come join us tackle important mechanistic questions in inflammatory signaling. Please share or apply!

careers.gene.com/us/en/job/20...

Postdoctoral Fellow - Structural Biology, Deshpande Lab in South San Francisco, California, United States of America | Students & Graduates at Genentech

Apply for Postdoctoral Fellow - Structural Biology, Deshpande Lab job with Genentech in South San Francisco, California, United States of America. Students & Graduates at Genentech

careers.gene.com

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Reposted by Matt Howard

Vijay Ramani @vram142.bsky.social · Mar 26

Beautiful work from our colleagues in the Jura & Verba labs here @ UCSF! Cryo-EM structures of PI3Ka / KRas complex in context of lipid nanodiscs. Read on for unexpected dimers & to see how high-rez structural biology w/ the right reconstitutions can inform mechanism! www.biorxiv.org/content/10.1...

Structures of the PI3Kα/KRas complex on lipid bilayers reveal the molecular mechanism of PI3Kα activation

PI3Kα is a potent oncogene that converts PIP2 to PIP3 at the plasma membrane upon activation by receptor tyrosine kinases and Ras GTPases. In the absence of any structures of activated PI3Kα, the mole...

www.biorxiv.org

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Reposted by Matt Howard

Carolyn Bertozzi @carolynbertozzi.bskyverified.social · Mar 5

It is important at this pivotal moment to @standupforscience.bsky.social. Looking forward to sharing my thoughts on why this should be a national priority at tomorrow’s rally in SF:

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Reposted by Matt Howard

Emily Blythe @emilyblythe.bsky.social · Feb 27

New preprint! Here, we explore how endocytosis encodes receptor-specific cAMP/PKA signaling downstream of three endogenously coexpressed GPCRs. www.biorxiv.org/content/10.1...

Endocytosis sculpts distinct cAMP signal transduction by endogenously coexpressed GPCRs

Many G protein-coupled receptors (GPCRs) trigger a second phase of G protein-dependent signaling from internal membranes after agonist-induced endocytosis. However, individual GPCRs differ significant...

www.biorxiv.org

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Reposted by Matt Howard

Ruth Huttenhain @rhuttenhain.bsky.social · Feb 24

My lab at
@stanfordmedicine.bsky.social
is recruiting! We are looking for a postdoc at the interface of quantitative proteomics and G protein-coupled receptor (GPCR) biology: postdocs.stanford.edu/prospective/...
#TeamMassSpec #Proteomics #GPCR #Postdoc

Open Postdoctoral position, faculty mentor Ruth Huttenhain | Office of Postdoctoral Affairs

postdocs.stanford.edu

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Matt Howard @matthewkhoward.bsky.social · Jan 8

Thanks Reid! Looks like they are queued to release with the next PDB update on Jan. 15

Reposted by Matt Howard

Vijay Ramani @vram142.bsky.social · Jan 2

Congrats @willowcoyote.bsky.social @amanglik.bsky.social and all authors on a tour de force dissection of proton-sensing by GPCRs! DMS, cryo-EM, MD -- it has it all! www.cell.com/cell/fulltex...

Molecular basis of proton sensing by G protein-coupled receptors

Howard et al. combine mechanistic deep mutational scanning, cryo-EM, and constant-pH molecular dynamics simulations to provide a holistic view of proton activation in human pH-sensitive GPCRs.

www.cell.com

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Matt Howard @matthewkhoward.bsky.social · Jan 7

Thanks Stephanie! Hope all is going will w/your new lab - excited to see all the amazing work to come!

Matt Howard @matthewkhoward.bsky.social · Jan 7

Thanks Joe!

Matt Howard @matthewkhoward.bsky.social · Jan 7

Thanks, glad you enjoyed it!

Matt Howard @matthewkhoward.bsky.social · Jan 7

Thanks Alex!

Matt Howard @matthewkhoward.bsky.social · Jan 6

Thanks for the invite! Excited to share some of our recent work tomorrow 😀

Atlas of Variant Effects Alliance @varianteffect.bsky.social · Jan 4

Welcome to the first Variant Effects Seminar Series of 2025! Kicking off on Jan 7 with two amazing speakers: Ujjwal Rathore and Matthew Howard. Don’t miss it! varianteffect.org/seminar-series
#FunctionalGenomics #Seminar

Matt Howard @matthewkhoward.bsky.social · Jan 6

Tagging all the folks who I can find here... @amanglik.bsky.social @willowcoyote.bsky.social @justingenglish.bsky.social @delemottelab.bsky.social ...

Matt Howard @matthewkhoward.bsky.social · Jan 6

Thanks @justingenglish.bsky.social!! Awesome working with you and excited to see where we go in the future 👀

Justin English @justingenglish.bsky.social · Jan 2

Groundbreaking work by @matthewkhoward.bsky.social and Nicholas Hoppe (not on bsky?) from the @willowcoyote.bsky.social @amanglik.bsky.social labs.

Mapping function to structure with deep mutational scanning to resolve the mechanisms of pH sensing GPCRs

www.sciencedirect.com/science/arti...

Molecular basis of proton sensing by G protein-coupled receptors

Three proton-sensing G protein-coupled receptors (GPCRs)—GPR4, GPR65, and GPR68—respond to extracellular pH to regulate diverse physiology. How proton…

www.sciencedirect.com

Matt Howard @matthewkhoward.bsky.social · Jan 6

There is certainly more than can be shared here, but I will end it there with a HUGE thanks to everyone involved! This was both a challenging and fun project to be involved in with many great folks without which none of this would be possible. (13/13)

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Matt Howard @matthewkhoward.bsky.social · Jan 6

Ultimately, this enabled us to identify residues which change pronation with conformation and pH. Combining our DMS, cryo-EM, MD, and extensive pharmacologic validation (by XP Huang), we were able to devise a comprehensive model for pH activation of GPR68 (12/n)

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Matt Howard @matthewkhoward.bsky.social · Jan 6

Well, Darko went above and beyond. He developed a new method which uses coevolutionary information to identify both alternative receptor conformations AND the effect of pH on the conformational ensemble. (11/n)

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Matt Howard @matthewkhoward.bsky.social · Jan 6

We needed an inactive-state structure model to fully interpret our results, so we teamed up with
Darko Mitrovic (in @delemottelab.bsky.social lab) to do some molecular dynamics simulations of GPR68 (10/n)

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Matt Howard @matthewkhoward.bsky.social · Jan 6

We followed up with a surface expression screen to determine the which mutations alter receptor expression. This allowed to deconvolve the mutational effects on expression vs activation to uncover GOF and LOF activity specific to activation. (9/n)

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Matt Howard @matthewkhoward.bsky.social · Jan 6

The result: a comprehensive map of each mutation's effect on pH activation. (8/n)

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Matt Howard @matthewkhoward.bsky.social · Jan 6

We then generated a mutational library of GPR68 using the DIMPLE platform developed in @willowcoyote.bsky.social's lab and screened it using our cAMP FACS assay (7/n)

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Matt Howard @matthewkhoward.bsky.social · Jan 6

Using GPR68 as our model, we set out to use mutational scanning to determine the effect of every mutation on proton activation. We developed a new FACS-based method to measure Gs coupled receptor activation (enabled by a new TRE's from @justingenglish.bsky.social ) (6/n)

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Matt Howard @matthewkhoward.bsky.social · Jan 6

We needed to ascribe a functional role for each residue in proton activation. Unfortunately, these receptors are littered with an enormous number polar and charged residues which may be implicated. (5/n)

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