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Matt Howard

@matthewkhoward.bsky.social
172 followers 257 following 23 posts

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

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Reposted by Matt Howard
Annual Reviews @annualreviews.bsky.social · 20/08/2026
The 2026 volume of the Annual Review of Biomedical Data Science is now available. The most downloaded article so far is "Mechanistic Mutational Scanning to Uncover the Secret Life of Proteins" by @matthewkhoward.bsky.social and @willowcoyote.bsky.social. Read it here bit.ly/3ULlwgT
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Reposted by Matt Howard
Willow Coyote-Maestas @willowcoyote.bsky.social · 09/07/2026
For the last 5 years, my lab has focused on developing mutational scanning methods and learning how to answer specific questions in protein biology. @matthewkhoward.bsky.social and I wrote a review on experimental decisions and future directions for our nascent field! doi.org/10.1146/annu...
annualreviews.org
Mechanistic Mutational Scanning to Uncover the Secret Life of Proteins
Deep mutational scanning (DMS) has emerged as a transformative tool for dissecting individual protein function and broader cell biology. DMS methods enable comprehensive interrogation of sequence–func...
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Reposted by Matt Howard
Jerome @jeromics.bsky.social · 26/02/2026
Happy to see this work out now in Genome Biology! Check out the final version here for your FACS DMS needs: link.springer.com/article/10.1...
link.springer.com
Accurate variant effect estimation in FACS-based deep mutational scanning data with Lilace - Genome Biology
Deep mutational scanning (DMS) coupled with fluorescence-activated cell sorting (FACS) provides a high-throughput method to link genetic variants with quantitative molecular phenotypes. Analysis of th...
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Reposted by Matt Howard
Willow Coyote-Maestas @willowcoyote.bsky.social · 20/02/2026
A wonderful first for me at the upcoming @biophysicalsoc.bsky.social meeting in SF is having many lab members present! See 6 brilliant graduate students postdocs from the lab present talks and posters on how they are pushing the boundaries of technology and mechanistic membrane protein biology
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Matt Howard @matthewkhoward.bsky.social · 21/07/2025
Congratulations!! 🥳
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Matt Howard @matthewkhoward.bsky.social · 30/06/2025
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 :)
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Reposted by Matt Howard
Ishan Deshpande @ishand.bsky.social · 26/03/2025
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...
careers.gene.com
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
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Reposted by Matt Howard
Vijay Ramani @vram142.bsky.social · 26/03/2025
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...
biorxiv.org
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...
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Reposted by Matt Howard
Carolyn Bertozzi @carolynbertozzi.bskyverified.social · 05/03/2025
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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Emily Blythe @emilyblythe.bsky.social · 27/02/2025
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...
biorxiv.org
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...
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Reposted by Matt Howard
Ruth Huttenhain @rhuttenhain.bsky.social · 24/02/2025
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
postdocs.stanford.edu
Open Postdoctoral position, faculty mentor Ruth Huttenhain | Office of Postdoctoral Affairs
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Matt Howard @matthewkhoward.bsky.social · 08/01/2025
Thanks Reid! Looks like they are queued to release with the next PDB update on Jan. 15
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Reposted by Matt Howard
Vijay Ramani @vram142.bsky.social · 02/01/2025
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...
cell.com
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.
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Matt Howard @matthewkhoward.bsky.social · 07/01/2025
Thanks Stephanie! Hope all is going will w/your new lab - excited to see all the amazing work to come!
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Matt Howard @matthewkhoward.bsky.social · 07/01/2025
Thanks Joe!
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Matt Howard @matthewkhoward.bsky.social · 07/01/2025
Thanks, glad you enjoyed it!
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Matt Howard @matthewkhoward.bsky.social · 07/01/2025
Thanks Alex!
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Matt Howard @matthewkhoward.bsky.social · 06/01/2025
Thanks for the invite! Excited to share some of our recent work tomorrow 😀
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Matt Howard @matthewkhoward.bsky.social · 06/01/2025
Tagging all the folks who I can find here... @amanglik.bsky.social @willowcoyote.bsky.social @justingenglish.bsky.social @delemottelab.bsky.social ...
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Matt Howard @matthewkhoward.bsky.social · 06/01/2025
Thanks @justingenglish.bsky.social!! Awesome working with you and excited to see where we go in the future 👀
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Matt Howard @matthewkhoward.bsky.social · 06/01/2025
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 · 06/01/2025
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 · 06/01/2025
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 · 06/01/2025
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 · 06/01/2025
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 · 06/01/2025
The result: a comprehensive map of each mutation's effect on pH activation. (8/n)
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Matt Howard @matthewkhoward.bsky.social · 06/01/2025
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 · 06/01/2025
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 · 06/01/2025
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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Matt Howard @matthewkhoward.bsky.social · 06/01/2025
To start, Nick Hoppe (in @amanglik.bsky.social's lab) set out to determine the 3D architecture of each human proton sensor (GPR4, GPR65, and GPR68) using cryo-EM. These provided insights into the architecture and arrangement of putative proton-sensing residues in the active-state (4/n)
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Matt Howard @matthewkhoward.bsky.social · 06/01/2025
We wanted to determine the location and identities of all residues involved in coordinating protons to drive receptor activation. (3/n)
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Matt Howard @matthewkhoward.bsky.social · 06/01/2025
We have known for some time that several GPCRs respond to changes in pH. However, unlike small molecules, peptides, and other stimuli, protons are a bit wonky--we can't directly see them with standard approaches. (2/n)
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Matt Howard @matthewkhoward.bsky.social · 06/01/2025
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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Reposted by Matt Howard
Justin English @justingenglish.bsky.social · 28/11/2024
Happy Thanksgiving y'all! I'm thankful for my whole lab, team, and collaborators this year. Our updated and final version of the TRE MPRA system is online today. If you have time between turkey bites have a gander. rdcu.be/d1OTf
rdcu.be
A massively parallel reporter assay library to screen short synthetic promoters in mammalian cells
Nature Communications - Context-dependent, responsive synthetic promoters are crucial for a wide range of applications, yet currently available options are limited. Here, authors develop a library...
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