The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index.
Peptide lipidation stabilizes structure to enhance biological function
Open accessAbstract
Medicines that decrease body weight and restore nutrient tolerance could improve human diabetes and obesity treatment outcomes. We developed lipid-acylated glucagon analogs that are co-agonists for the glucagon and glucagon-like peptide 1 receptors, and stimulate weight loss and plasma glucose lowering in pre-diabetic obese mice. Our studies identified lipid acylation (lipidation) can increase and balance in vitro potencies of select glucagon analogs for the two aforementioned receptors in a lipidation site-dependent manner. A general capacity for lipidation to enhance the secondary structure of glucagon analogs was recognized, and the energetics of this effect quantified. The molecular structure of a lipid-acylated glucagon analog in water was also characterized. These results support that lipidation can modify biological activity through thermodynamically-favorable intramolecular interactions which stabilize structure. This establishes use of lipidation to achieve specific pharmacology and implicates similar endogenous post-translational modifications as physiological tools capable of refining biological action in means previously underappreciated.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Importantly, this demonstrates that the chemical nature of the acylation influences not only the pharmacokinetics of the peptide but also the pharmacophore itself, which further highlights that such modifications are not inert bystanders with respect to biological activity [48] and biodistribution [49].”
From Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice (2022) · cites this paper as [48]
Citations
Cites
NMRPipe: A multidimensional spectral processing system based on UNIX pipes
Delaglio, F., Grzesiek, S., Vuister, G. W., Zhu, G., Pfeifer, J., & Bax, A. (1995) · Journal of Biomolecular NMR · doi:10.1007/bf00197809 · Cited by 15,961
NMR with Proteins and Nucleic Acids
Wüthrich, K. (1986) · Europhysics news · doi:10.1051/epn/19861701011 · Cited by 8,028
NMR of Proteins and Nucleic Acids
(2006) · Royal Society of Chemistry eBooks · doi:10.1039/9781847555236-00336 · Cited by 5,874
Using circular dichroism spectra to estimate protein secondary structure
Greenfield, N. J. (2006) · Nature Protocols · doi:10.1038/nprot.2006.202 · Cited by 4,123
Solid phase peptide synthesis utilizing 9‐fluorenylmethoxycarbonyl amino acids
Fields, G., & NOBLE, R. L. (1990) · International journal of peptide & protein research · doi:10.1111/j.1399-3011.1990.tb00939.x · Cited by 2,490
The Xplor-NIH NMR molecular structure determination package
Schwieters, C. D., Kuszewski, J. J., Tjandra, N., & Clore, G. M. (2003) · Journal of Magnetic Resonance · doi:10.1016/s1090-7807(02)00014-9 · Cited by 2,371
Ulrich, E. L., Akutsu, H., Doreleijers, J. F., Harano, Y., Ioannidis, Y., Lin, J. C., Livny, M., Mading, S., Maziuk, D., Miller, Z., et al. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm957 · Cited by 1,472
Molecular and Cellular Endocrinology
Rainey, W. E., & Rodgers, R. J. (2004) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2004.10.007 · Cited by 1,340
Greenfield, N. J. (2006) · Nature Protocols · doi:10.1038/nprot.2006.204 · Cited by 886
Knudsen, L. B., Nielsen, P. F., Huusfeldt, P. O., Johansen, N. L., Madsen, K., Pedersen, F. Z., Thøgersen, H., Wilken, M., & Agersø, H. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm9909645 · Cited by 711
A new glucagon and GLP-1 co-agonist eliminates obesity in rodents
Day, J. W., Ottaway, N., Patterson, J. T., Gelfanov, V., Smiley, D., Gidda, J., Findeisen, H., Bruemmer, D., Drucker, D. J., Chaudhary, N., et al. (2009) · Nature Chemical Biology · doi:10.1038/nchembio.209 · Cited by 641
Self-citationPrinciples of physical biochemistry
Holde, K. E. V., Johnson, W. C., & Ho, P. S. (1998) · Cited by 580
Neural palmitoyl-proteomics reveals dynamic synaptic palmitoylation
Kang, R., Wan, J., Arstikaitis, P., Takahashi, H., Huang, K., Bailey, A. O., Thompson, J. X., Roth, A. F., Drisdel, R. C., Mastro, R., et al. (2008) · Nature · doi:10.1038/nature07605 · Cited by 533
Large-scale profiling of protein palmitoylation in mammalian cells
Martin, B. R., & Cravatt, B. F. (2009) · Nature Methods · doi:10.1038/nmeth.1293 · Cited by 511
The Mechanism of Protraction of Insulin Detemir, a Long-Acting, Acylated Analog of Human Insulin
Havelund, S., Plum, A., Ribel, U., Jonassen, I., Vølund, A., Markussen, J., & Kurtzhals, P. (2004) · Pharmaceutical Research · doi:10.1023/b:pham.0000036926.54824.37 · Cited by 431
Glucagon-Like Peptide 1/Glucagon Receptor Dual Agonism Reverses Obesity in Mice
Pocai, A., Carrington, P. E., Adams, J. R., Wright, M., Eiermann, G., Zhu, L., Du, X., Petrov, A., Lassman, M. E., Jiang, G., et al. (2009) · Diabetes · doi:10.2337/db09-0278 · Cited by 409
Protein palmitoylation and subcellular trafficking
Aicart-Ramos, C., Valero, R. A., & Rodríguez‐Crespo, I. (2011) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2011.07.009 · Cited by 387
Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation
Lin, D.-T., Makino, Y., Sharma, K., Hayashi, T., Neve, R., Takamiya, K., & Huganir, R. L. (2009) · Nature Neuroscience · doi:10.1038/nn.2351 · Cited by 347
Conformation of glucagon in a lipid-water interphase by 1H nuclear magnetic resonance
Braun, W. A., Wider, G., Lee, K. H., & Kurt Wüthrich, A. (1983) · Journal of Molecular Biology · doi:10.1016/s0022-2836(83)80143-0 · Cited by 340
Structure-activity studies of glucagon-like peptide-1.
Adelhorst, K., Hedegaard, B. B., Knudsen, L. B., & Kirk, O. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)37366-0 · Cited by 286
Kanoski, S. E., Rupprecht, L. E., Fortin, S. M., De Jonghe, B. C., & Hayes, M. R. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.12.022 · Cited by 273
Evaluation of a Quantitative Magnetic Resonance Method for Mouse Whole Body Composition Analysis
Tinsley, F. C., Taicher, G. Z., & Heiman, M. L. (2004) · Obesity Research · doi:10.1038/oby.2004.20 · Cited by 244
Madsen, K., Knudsen, L. B., Agersoe, H., Nielsen, P. F., Thøgersen, H., Wilken, M., & Johansen, N. L. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm070861j · Cited by 244
Passing the baton in class B GPCRs: peptide hormone activation via helix induction?
Parthier, C., Reedtz‐Runge, S., Rudolph, R., & Stubbs, M. T. (2009) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2009.02.004 · Cited by 193
Dynamic structure of membrane-anchored Arf•GTP
Liu, Y., Kahn, R., & Prestegard, J. H. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1853 · Cited by 139
Molecular, pharmacological and clinical aspects of liraglutide, a once-daily human GLP-1 analogue
Russell-Jones, D. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.11.018 · Cited by 137
Day, J. W., Gelfanov, V., Smiley, D., Carrington, P. E., Eiermann, G., Chicchi, G., Erion, M. D., Gidda, J., Thornberry, N. A., Tschöp, M. H., et al. (2012) · Peptide Science · doi:10.1002/bip.22072 · Cited by 133
Self-citationEffect of Phosphorylation on α-Helix Stability as a Function of Position
Andrew, C. D., Warwicker, J., Jones, G. R., & Doig, A. J. (2002) · Biochemistry · doi:10.1021/bi0113216 · Cited by 133
Reiersen, H., & Rees, A. R. (2000) · Protein Engineering Design and Selection · doi:10.1093/protein/13.11.739 · Cited by 119
Moffett, S., Adam, L., Bonin, H., Loisel, T. P., Bouvier, M., & Mouillac, B. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.35.21490 · Cited by 114
[1] Concept and early development of solid-phase peptide synthesis
Merrifield, R. B. (1997) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(97)89040-4 · Cited by 106
Thornton, K. H., & Gorenstein, D. G. (1994) · Biochemistry · doi:10.1021/bi00178a009 · Cited by 102
Charych, E. I., Jiang, L.-X., Lo, F., Sullivan, K., & Brandon, N. J. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1635-10.2010 · Cited by 98
Johansson, J., Nilsson, G., Strömberg, R., Robertson, B., Jörnvall, H., & Curstedt, T. (1995) · Biochemical Journal · doi:10.1042/bj3070535 · Cited by 93
Phosphorylation destabilizes α-helices
Szilák, L., Moitra, J., Krylov, D. Y., & Vinson, C. (1997) · Nature Structural Biology · doi:10.1038/nsb0297-112 · Cited by 84
Multiple-site replacement analogs of glucagon. A molecular basis for antagonist design.
Unson, C. G., Wu, C. R., Fitzpatrick, K., & Merrifield, R. B. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)99910-2 · Cited by 45
Farnesylation of the SNARE Protein Ykt6 Increases Its Stability and Helical Folding
Pylypenko, O., Schönichen, A., Ludwig, D., Ungermann, C., Goody, R. S., Rak, A., & Geyer, M. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.01.099 · Cited by 43
Krstenansky, J. L., Trivedi, D. B., & Hruby, V. J. (1986) · Biochemistry · doi:10.1021/bi00361a014 · Cited by 39
Alaña, I., Malthouse, J. P. G., O'Harte, F. P. M., & Hewage, C. M. (2007) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.21372 · Cited by 35
Site-specific Effects of Peptide Lipidation on β-Amyloid Aggregation and Cytotoxicity
Qahwash, I. M., Boire, A. A., Lanning, J. D., Krausz, T. N., Pytel, P., & Meredith, S. C. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702146200 · Cited by 22
Unson, C. G., Wu, C.-R., Cheung, C. P., & Merrifield, R. B. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.17.10308 · Cited by 22
Patterson, J. T., Day, J. W., Gelfanov, V. M., & DiMarchi, R. D. (2011) · Journal of Peptide Science · doi:10.1002/psc.1385 · Cited by 16
Self-citationStabilization of conformationally dynamic helices by covalently attached acyl chains
Poschner, B. C., & Langosch, D. (2009) · Protein Science · doi:10.1002/pro.155 · Cited by 13
Cited by
Sorted by citations
A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents
Finan, B., Yang, B., Ottaway, N., Smiley, D. L., Ma, T., Clemmensen, C., Chabenne, J., Zhang, L., Habegger, K. M., Fischer, K., et al. (2015) · Nature Medicine · doi:10.1038/nm.3761 · Cited by 645
Self-citationFactors affecting the physical stability (aggregation) of peptide therapeutics
Zapadka, K. L., Becher, F. J., dos Santos, A. L. G., & Jackson, S. (2017) · Interface Focus · doi:10.1098/rsfs.2017.0030 · Cited by 425
Prebiotic Peptides: Molecular Hubs in the Origin of Life
Frenkel-Pinter, M., Samanta, M., Ashkenasy, G., & Leman, L. J. (2020) · Chemical Reviews · doi:10.1021/acs.chemrev.9b00664 · Cited by 354
Peptide chemistry toolbox – Transforming natural peptides into peptide therapeutics
Erak, M., Bellmann‐Sickert, K., Els‐Heindl, S., & Beck‐Sickinger, A. G. (2018) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2018.01.012 · Cited by 327
Antimicrobial peptides: an alternative for innovative medicines?
da Costa, J. P., Cova, M. M., Ferreira, R. M., & Vitorino, R. M. P. (2015) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-015-6375-x · Cited by 212
Metadata
- Authors
- Ward, B. P., Ottaway, N. L., Perez-Tilve, D., Ma, D., Gelfanov, V. M., Tschöp, M. H., & DiMarchi, R. D.
- Affiliations
- Indiana University Bloomington (US)
- University of Cincinnati (US)
- Helmholtz Munich (DE)
- Corresponding author
- Ward, Brian P.
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 2
- Issue
- 4
- Pages
- 468-479
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC3854995
- OpenAlex
- W2047944726
- Cited by
- 101
- References
- 43
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 12 · 2021: 10 · 2020: 9 · 2019: 10 · 2018: 10 · 2017: 9 · 2016: 8 · 2015: 6 · 2014: 4
- FWCI
- 4.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion, cc-by-nc-nd)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- glucagon receptor, GLP-1 receptor, weight loss, blood glucose reduction, obesity, diabetes mellitus, prediabetes, intramolecular interactions, post-translational modification, structure-activity relationship
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review