Joel Walker’s Post

Together with John Auchampach’s lab (Medical College of Wisconsin), we introduce the approach of lipid trolling, to derivatize #GPCR ligands that bind at sites in contact with membrane lipids. A3 #adenosine #receptor positive allosteric modulators (#PAMs) occupy a membrane-exposed, cryptic binding site. Analogues that penetrate further into the #phospholipid environment utilize a hydrocarbon (hydrophobic) chain that is functionalized with a terminal cationic group (an amine, guanidino group, etc.), to anchor it to anionic head groups in the membrane inner leaflet. There’s a clear dependence of PAM potency on the chain length (with optima at 10 or 11 carbons). Analogues with uncharged appended chains are essentially inactive, because they lack a stabilizing second anchor (shown by molecular dynamics simulation by Matteo Pavan). In this manner the PAM pharmacological activity is qualitatively enhanced. https://lnkd.in/eEaCvSAy

Further development of adenosine receptor positive allosteric modulators in collaboration with the Jacobson lab at the NIH and introduction of the concept of 'lipid trolling' to optimize molecular interactions with a lipid-exposed transmembrane protein binding site. https://lnkd.in/gmse4VPZ

Lipopolysaccharide (LPS) is a major component of the outer leaflet of the outer membrane (OM) of Gram-negative bacteria. Lipid A functions as the hydrophobic membrane anchor of LPS and is linked via a core oligosaccharide to the long chain polysaccharide known as O-antigen. The lipid A-core portion (known as “rough” LPS (R-LPS)) is synthesized by a conserved pathway involving proteins on the cytoplasmic surface of the inner membrane (IM) and is then transported across the IM by an essential ATP-binding cassette (ABC) transporter, MsbA. Recently, five additional essential E. coli proteins (LptA, LptB, LptC (formerly YrbK), LptF (formerly YjgP), and LptG (formerly YjgQ)) have been implicated in LPS transport to the OM. LptA is a candidate for the chaperone delivering nascent LPS molecules to LptDE in the OM. Here you can see a recent crystal structure of the LptA protein from Escherichia coli (PDB code: 8GAJ) Rendering by Francisco J. Enguita made with #proteinimager https://lnkd.in/dhGeg77z #molecularart #periplasm #gramnegative #cellwall #LptA #peptidoglycan #xray

Lipopolysaccharide (LPS) is a major component of the outer leaflet of the outer membrane (OM) of Gram-negative bacteria. Lipid A functions as the hydrophobic membrane anchor of LPS and is linked via a core oligosaccharide to the long chain polysaccharide known as O-antigen. The lipid A-core portion (known as “rough” LPS (R-LPS)) is synthesized by a conserved pathway involving proteins on the cytoplasmic surface of the inner membrane (IM) and is then transported across the IM by an essential ATP-binding cassette (ABC) transporter, MsbA. Recently, five additional essential E. coli proteins (LptA, LptB, LptC (formerly YrbK), LptF (formerly YjgP), and LptG (formerly YjgQ)) have been implicated in LPS transport to the OM. LptA is a candidate for the chaperone delivering nascent LPS molecules to LptDE in the OM. Here you can see a recent crystal structure of the LptA protein from Escherichia coli (PDB code: 8GAJ) Rendering by Francisco J. Enguita made with #proteinimager https://lnkd.in/dzCVhWUe #molecularart #periplasm #gramnegative #cellwall #LptA #peptidoglycan #xray

Excipient Impact on Fenofibrate Equilibrium Solubility in Fasted and Fed Simulated Intestinal Fluids Assessed Using a Design of Experiment Protocol

Don’t choose between speed and sensitivity. ⚡🔬 Our Lumi-Phos PRO substrate comes to full glow in under one minute, accelerating the time to first result by 5 minutes for every Access Immunoassay assay. ⏱️ The new substrate has been optimized to rapidly generate signal, improve signal-to-noise performance, and reduce interference from endogenous alkaline phosphatase (ALP). 📈🔍 https://bit.ly/3VJ4ZqP

Inhibition of PCSK9-LDLR interaction has emerged as a promising therapeutic strategy to manage hypercholesterolemia However, when it comes to small molecule PCSK9 inhibitors, it's the large interaction surface area between PCSK9 and LDLR makes it challenging to identify a competitive inhibitor. An alternative strategy would be to identify distal cryptic sites as targets for allosteric inhibitors that can remotely modulate PCSK9-LDLR interaction. This work provides a general strategy toward identifying allosteric hotspots: compare the conformational ensemble of the receptor between the apo and bound states of the protein and identify distal conformational changes, if any.

New Post: A Full Analysis Of Two Peptides - https://lnkd.in/dRjaiz-F

Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death - https://lnkd.in/gTUQZTwd This is a very thorough review in which the enzyme is my current theme of work in the lab! Im so proud of being part of it, first paper in jmedchem!

A new paper on complex formation in pattern formation has been published. The trichome patterning process shows that 26 complexes can be expected from only 4 binding proteins, indicating differential activities in the patterning network. The overarching questions in pattern formation and self-organisation include how to handle this complexity and derive conceptual understanding.  Check out our publication: https://lnkd.in/e8PHPnZK