Doctor of Philosophy, University of Wisconsin Madison (2022)
Bachelor of Arts, Macalester College, Applied Mathematics, Chemistry (2017)
Lynette Cegelski, Postdoctoral Faculty Sponsor
- Tailoring Reaction Selectivity by Modulating a Catalytic Diad on a Foldamer Scaffold (vol 144, pg 2225, 2022) JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 2022; 144 (34): 15908
Structural and functional diversity among agonist-bound states of the GLP-1 receptor
NATURE CHEMICAL BIOLOGY
2022; 18 (3): 256-+
Recent advances in G-protein-coupled receptor (GPCR) structural elucidation have strengthened previous hypotheses that multidimensional signal propagation mediated by these receptors depends, in part, on their conformational mobility; however, the relationship between receptor function and static structures is inherently uncertain. Here, we examine the contribution of peptide agonist conformational plasticity to activation of the glucagon-like peptide 1 receptor (GLP-1R), an important clinical target. We use variants of the peptides GLP-1 and exendin-4 (Ex4) to explore the interplay between helical propensity near the agonist N terminus and the ability to bind to and activate the receptor. Cryo-EM analysis of a complex involving an Ex4 analog, the GLP-1R and Gs heterotrimer revealed two receptor conformers with distinct modes of peptide-receptor engagement. Our functional and structural data, along with molecular dynamics (MD) simulations, suggest that receptor conformational dynamics associated with flexibility of the peptide N-terminal activation domain may be a key determinant of agonist efficacy.
View details for DOI 10.1038/s41589-021-00945-w
View details for Web of Science ID 000733335800005
View details for PubMedID 34937906
View details for PubMedCentralID PMC8950777
Comparisons of beta-Hairpin Propensity Among Peptides with Homochiral or Heterochiral Strands
2021; 22 (18): 2772-2776
Assemblies of racemic β-sheet-forming peptides have attracted attention for biomedical applications because racemic forms of peptides can self-associate more avidly than do single enantiomers. In 1953, Pauling and Corey proposed "rippled β-sheet" modes of H-bond-mediated interstrand assembly for alternating L- and D-peptide strands; this structural hypothesis was complementary to their proposal of "pleated β-sheet" assembly for L-peptides. Although no high-resolution structure has been reported for a rippled β-sheet, there is strong evidence for the occurrence of rippled β-sheets in some racemic peptide assemblies. Here we compare propensities of peptide diastereomers in aqueous solution to form a minimum increment of β-sheet in which two antiparallel strands associate. β-Hairpin folding is observed for homochiral peptides with aligned nonpolar side chains, but no β-hairpin population can be detected for diastereomers in which one strand contains L residues and the other contains D residues. These observations suggest that rippled β-sheet assemblies are stabilized by interactions between β-sheet layers rather than interactions within these layers.
View details for DOI 10.1002/cbic.202100324
View details for Web of Science ID 000679561600001
View details for PubMedID 34288305
View details for PubMedCentralID PMC8486351
The role of beta-hairpin conformation in ester hydrolysis peptide catalysts based on a TrpZip scaffold
2021; 11 (38): 23714-23718
To explore the role of peptide conformation on catalytic activity in the context of ester hydrolysis catalysts, pairs of sequences were designed that contained or lacked β-hairpin character. For the hydrolysis of para-nitrophenylacetate in aqueous media, we found small but consistent trends wherein His-containing sequences based on a TrpZip scaffold showed higher catalytic activity without β-hairpin character.
View details for DOI 10.1039/d1ra04288b
View details for Web of Science ID 000671447100056
View details for PubMedID 34354822
View details for PubMedCentralID PMC8285361
Catalytic Intramolecular Conjugate Additions of Aldehyde-Derived Enamines to alpha,beta-Unsaturated Esters
2020; 22 (11): 4568-4573
We report a pairing of known catalysts that enables intramolecular conjugate additions of aldehyde-derived enamines to α,β-unsaturated esters. Despite extensive prior exploration of conjugate additions of aldehyde-derived enamines, catalytic conjugate additions to unactivated enoate esters are unprecedented. Achieving enantioselective and diastereoselective six-membered ring formation requires the coordinated action of a chiral pyrrolidine, for nucleophilic activation of the aldehyde via enamine formation, and a hydrogen bond donor, for electrophilic activation of the enoate ester. Proper selection of the hydrogen bond donor is essential for chemoselectivity, which requires minimizing competition from homoaldol reaction. Utility is demonstrated in a six-step synthesis of (-)-yohimbane from cycloheptene.
View details for DOI 10.1021/acs.orglett.0c01666
View details for Web of Science ID 000538848600099
View details for PubMedID 32460501
Foldamer-templated catalysis of macrocycle formation
2019; 366 (6472): 1528-+
Macrocycles, compounds containing a ring of 12 or more atoms, find use in human medicine, fragrances, and biological ion sensing. The efficient preparation of macrocycles is a fundamental challenge in synthetic organic chemistry because the high entropic cost of large-ring closure allows undesired intermolecular reactions to compete. Here, we present a bioinspired strategy for macrocycle formation through carbon-carbon bond formation. The process relies on a catalytic oligomer containing α- and β-amino acid residues to template the ring-closing process. The α/β-peptide foldamer adopts a helical conformation that displays a catalytic primary amine-secondary amine diad in a specific three-dimensional arrangement. This catalyst promotes aldol reactions that form rings containing 14 to 22 atoms. Utility is demonstrated in the synthesis of the natural product robustol.
View details for DOI 10.1126/science.aax7344
View details for Web of Science ID 000503861000058
View details for PubMedID 31857487
View details for PubMedCentralID PMC7956107
A colorimetric competitive displacement assay for the evaluation of catalytic peptides
ORGANIC & BIOMOLECULAR CHEMISTRY
2017; 15 (48): 10160-10163
An indicator displacement assay has been adapted to detect the diol products of the aldol reaction between 4-nitrobenzaldehyde and hydroxyacetone in crude reaction mixtures. This provides a rapid colorimetric method of detecting product formation and thus evaluating potential catalysts, which is demonstrated using multiple catalytic peptides.
View details for DOI 10.1039/c7ob02032e
View details for Web of Science ID 000418070800005
View details for PubMedID 29182189
Pre-monomer peptidomimetic synthesis using thiol-ene click chemistry
AMER CHEMICAL SOC. 2017
View details for Web of Science ID 000430568505280