[ { "id": "authors:7akp4-6w269", "collection": "authors", "collection_id": "7akp4-6w269", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20171211-144538096", "type": "article", "title": "Predicting glycosaminoglycan surface protein interactions and implications for studying axonal growth", "author": [ { "family_name": "Griffith", "given_name": "Adam R.", "clpid": "Griffith-Adam-R" }, { "family_name": "Rogers", "given_name": "Claude J.", "clpid": "Rogers-Claude-J" }, { "family_name": "Miller", "given_name": "Gregory M.", "orcid": "0000-0002-7595-7996", "clpid": "Miller-Gregory-M" }, { "family_name": "Abrol", "given_name": "Ravinder", "orcid": "0000-0001-7333-6793", "clpid": "Abrol-Ravinder" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Goddard", "given_name": "William A., III", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" } ], "abstract": "Cell-surface carbohydrates play important roles in numerous biological processes through their interactions with various protein-binding partners. These interactions are made possible by the vast structural diversity of carbohydrates and the diverse array of carbohydrate presentations on the cell surface. Among the most complex and important carbohydrates are glycosaminoglycans (GAGs), which display varied stereochemistry, chain lengths, and patterns of sulfation. GAG\u2013protein interactions participate in neuronal development, angiogenesis, spinal cord injury, viral invasion, and immune response. Unfortunately, little structural information is available for these complexes; indeed, for the highly sulfated chondroitin sulfate motifs, CS-E and CS-D, there are no structural data. We describe here the development and validation of the GAG-Dock computational method to predict accurately the binding poses of protein-bound GAGs. We validate that GAG-Dock reproduces accurately (<1-\u00c5 rmsd) the crystal structure poses for four known heparin\u2013protein structures. Further, we predict the pose of heparin and chondroitin sulfate derivatives bound to the axon guidance proteins, protein tyrosine phosphatase \u03c3 (RPTP\u03c3), and Nogo receptors 1\u20133 (NgR1-3). Such predictions should be useful in understanding and interpreting the role of GAGs in neural development and axonal regeneration after CNS injury.", "doi": "10.1073/pnas.1715093115", "pmcid": "PMC5748211", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2017-12-26", "series_number": "52", "volume": "114", "issue": "52", "pages": "13697-13702" }, { "id": "authors:2rmxb-8cs16", "collection": "authors", "collection_id": "2rmxb-8cs16", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170223-110325516", "type": "article", "title": "Activation mechanism of the G protein-coupled sweet receptor heterodimer with sweeteners and allosteric agonists", "author": [ { "family_name": "Kim", "given_name": "Soo-Kyung", "orcid": "0000-0002-4498-5441", "clpid": "Kim-Soo-Kyung" }, { "family_name": "Chen", "given_name": "Yalu", "orcid": "0000-0002-0589-845X", "clpid": "Chen-Yalu" }, { "family_name": "Abrol", "given_name": "Ravinder", "orcid": "0000-0001-7333-6793", "clpid": "Abrol-Ravinder" }, { "family_name": "Goddard", "given_name": "William A., III", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" }, { "family_name": "Guthrie", "given_name": "Brian", "orcid": "0000-0002-3508-4625", "clpid": "Guthrie-Brian" } ], "abstract": "The sweet taste in humans is mediated by the TAS1R2/TAS1R3 G protein-coupled receptor (GPCR), which belongs to the class C family that also includes the metabotropic glutamate and \u03b3-aminobutyric acid receptors. We report here the predicted 3D structure of the full-length TAS1R2/TAS1R3 heterodimer, including the Venus Flytrap Domains (VFDs) [in the closed\u2013open (co) active conformation], the cysteine-rich domains (CRDs), and the transmembrane domains (TMDs) at the TM56/TM56 interface. We observe that binding of agonists to VFD2 of TAS1R2 leads to major conformational changes to form a TM6/TM6 interface between TMDs of TAS1R2 and TAS1R3, which is consistent with the activation process observed biophysically on the metabotropic glutamate receptor 2 homodimer. We find that the initial effect of the agonist is to pull the bottom part of VFD3/TAS1R3 toward the bottom part of VFD2/TAS1R2 by \u223c6 \u00c5 and that these changes get transmitted from VFD2 of TAS1R2 (where agonists bind) through the VFD3 and the CRD3 to the TMD3 of TAS1R3 (which couples to the G protein). These structural transformations provide a detailed atomistic mechanism for the activation process in GPCR, providing insights and structural details that can now be validated through mutation experiments.", "doi": "10.1073/pnas.1700001114", "pmcid": "PMC5347580", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2017-03-07", "series_number": "10", "volume": "114", "issue": "10", "pages": "2568-2573" }, { "id": "authors:rfyjc-b9w89", "collection": "authors", "collection_id": "rfyjc-b9w89", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160526-095348614", "type": "article", "title": "Antifreeze proteins govern the precipitation of trehalose in a freezing-avoiding insect at low temperature", "author": [ { "family_name": "Wen", "given_name": "Xin", "orcid": "0000-0002-2465-7870", "clpid": "Wen-Xin" }, { "family_name": "Wang", "given_name": "Sen", "clpid": "Wang-Sen" }, { "family_name": "Duman", "given_name": "John G.", "clpid": "Duman-John-G" }, { "family_name": "Arifin", "given_name": "Josh Fnu", "clpid": "Arifin-Josh-Fnu" }, { "family_name": "Juwita", "given_name": "Vonny", "clpid": "Juwita-Vonny" }, { "family_name": "Goddard", "given_name": "William A., III", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" }, { "family_name": "Rios", "given_name": "Alejandra", "orcid": "0000-0003-4881-5324", "clpid": "Rios-Alejandra" }, { "family_name": "Liu", "given_name": "Fan", "orcid": "0000-0001-5650-2809", "clpid": "Liu-Fan" }, { "family_name": "Kim", "given_name": "Soo-Kyung", "orcid": "0000-0002-4498-5441", "clpid": "Kim-Soo-Kyung" }, { "family_name": "Abrol", "given_name": "Ravinder", "orcid": "0000-0001-7333-6793", "clpid": "Abrol-Ravinder" }, { "family_name": "DeVries", "given_name": "Arthur L.", "clpid": "DeVries-Athrur-L" }, { "family_name": "Henling", "given_name": "Lawrence M.", "clpid": "Henling-Lawrence-M" } ], "abstract": "The remarkable adaptive strategies of insects to extreme environments are linked to the biochemical compounds in their body fluids. Trehalose, a versatile sugar molecule, can accumulate to high levels in freeze-tolerant and freeze-avoiding insects, functioning as a cryoprotectant and a supercooling agent. Antifreeze proteins (AFPs), known to protect organisms from freezing by lowering the freezing temperature and deferring the growth of ice, are present at high levels in some freeze-avoiding insects in winter, and yet, paradoxically are found in some freeze-tolerant insects. Here, we report a previously unidentified role for AFPs in effectively inhibiting trehalose precipitation in the hemolymph (or blood) of overwintering beetle larvae. We determine the trehalose level (29.6 \u00b1 0.6 mg/mL) in the larval hemolymph of a beetle, Dendroides canadensis, and demonstrate that the hemolymph AFPs are crucial for inhibiting trehalose crystallization, whereas the presence of trehalose also enhances the antifreeze activity of AFPs. To dissect the molecular mechanism, we examine the molecular recognition between AFP and trehalose crystal interfaces using molecular dynamics simulations. The theory corroborates the experiments and shows preferential strong binding of the AFP to the fast growing surfaces of the sugar crystal. This newly uncovered role for AFPs may help explain the long-speculated role of AFPs in freeze-tolerant species. We propose that the presence of high levels of molecules important for survival but prone to precipitation in poikilotherms (their body temperature can vary considerably) needs a companion mechanism to prevent the precipitation and here present, to our knowledge, the first example. Such a combination of trehalose and AFPs also provides a novel approach for cold protection and for trehalose crystallization inhibition in industrial applications.", "doi": "10.1073/pnas.1601519113", "pmcid": "PMC4914155", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2016-06-14", "series_number": "24", "volume": "113", "issue": "24", "pages": "6683-6688" }, { "id": "authors:zf8kc-ftm48", "collection": "authors", "collection_id": "zf8kc-ftm48", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160111-104516976", "type": "article", "title": "Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Receptor", "author": [ { "family_name": "Scott", "given_name": "Caitlin E.", "clpid": "Scott-Caitlin-E" }, { "family_name": "Ahn", "given_name": "Kwang H.", "clpid": "Ahn-Kwang-H" }, { "family_name": "Graf", "given_name": "Steven T.", "clpid": "Graf-Steven-T" }, { "family_name": "Goddard", "given_name": "William A., III", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" }, { "family_name": "Kendall", "given_name": "Debra A.", "orcid": "0000-0002-4991-9953", "clpid": "Kendall-Debra-A" }, { "family_name": "Abrol", "given_name": "Ravinder", "orcid": "0000-0001-7333-6793", "clpid": "Abrol-Ravinder" } ], "abstract": "Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity. The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 [Scott, C. E. et al. Protein Sci. 2013, 22, 101\u2212113; Ahn, K. H. et al. Proteins 2013, 81, 1304\u20131317] are used here to predict the binding sites for known CB1-selective inverse agonists including rimonabant and its seven known derivatives. This binding pocket, which differs significantly from previously published models, is used to identify 16 novel compounds expected to be CB1 inverse agonists by exploiting potential new interactions. We show experimentally that two of these compounds exhibit inverse agonist properties including inhibition of basal and agonist-induced G-protein coupling activity, as well as an enhanced level of CB1 cell surface localization. This demonstrates the utility of using the predicted binding sites for an ensemble of CB1 receptor structures for designing new CB1 inverse agonists.", "doi": "10.1021/acs.jcim.5b00581", "pmcid": "PMC4863456", "issn": "1549-9596", "publisher": "American Chemical Society", "publication": "Journal of Chemical Information and Modeling", "publication_date": "2016-01-25", "series_number": "1", "volume": "56", "issue": "1", "pages": "201-212" }, { "id": "authors:xdjgn-mbx25", "collection": "authors", "collection_id": "xdjgn-mbx25", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140825-223735998", "type": "article", "title": "Ligand- and mutation-induced conformational selection in the CCR5 chemokine G protein-coupled receptor", "author": [ { "family_name": "Abrol", "given_name": "Ravinder", "orcid": "0000-0001-7333-6793", "clpid": "Abrol-Ravinder" }, { "family_name": "Trzaskowski", "given_name": "Bartosz", "clpid": "Trzaskowski-Bartosz" }, { "family_name": "Goddard", "given_name": "William A., III", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" }, { "family_name": "Nesterov", "given_name": "Alexandre", "clpid": "Nesterov-Alexandre" }, { "family_name": "Olave", "given_name": "Ivan", "clpid": "Olave-Ivan" }, { "family_name": "Irons", "given_name": "Christopher", "clpid": "Irons-Christopher" } ], "abstract": "We predicted the structural basis for pleiotropic signaling of the C-C chemokine type 5 (CCR5) G protein-coupled receptor (GPCR) by predicting the binding of several ligands to the lower-energy conformations of the CCR5 receptor and 11 mutants. For each case, we predicted the \u223c20 most stable conformations for the receptor along with the binding sites for four anti-HIV ligands. We found that none of the ligands bind to the lowest-energy apo-receptor conformation. The three ligands with a similar pharmacophore (Maraviroc, PF-232798, and Aplaviroc) bind to a specific higher-energy receptor conformation whereas TAK-779 (with a different pharmacophore) binds to a different high-energy conformation. This result is in agreement with the very different binding-site profiles for these ligands obtained by us and others. The predicted Maraviroc binding site agrees with the recent structure of CCR5 receptor cocrystallized with Maraviroc. We performed 11 site-directed mutagenesis experiments to validate the predicted binding sites. Here, we independently predicted the lowest 10 mutant protein conformations for each of the 11 mutants and then docked the ligands to these lowest conformations. We found the predicted binding energies to be in excellent agreement with our mutagenesis experiments. These results show that, for GPCRs, each ligand can stabilize a different protein conformation, complicating the use of cocrystallized structures for ligand screening. Moreover, these results show that a single-point mutation in a GPCR can dramatically alter the available low-energy conformations, which in turn alters the binding site, potentially altering downstream signaling events. These studies validate the conformational selection paradigm for the pleiotropic function and structural plasticity of GPCRs.", "doi": "10.1073/pnas.1413216111", "pmcid": "PMC4246978", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2014-09-09", "series_number": "36", "volume": "111", "issue": "36", "pages": "13040-13045" } ]