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The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla (2008)

J. S. McLellan ; X. Zheng ; G. Hauk ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 455(7215): 979-83. doi: 10.1038/nature07358.

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Publication Date: 2008-09-17

Description: Hedgehog (Hh) proteins specify tissue pattern in metazoan embryos by forming gradients that emanate from discrete sites of expression and elicit concentration-dependent cellular differentiation or proliferation responses. Cellular responses to Hh and the movement of Hh through tissues are both precisely regulated, and abnormal Hh signalling has been implicated in human birth defects and cancer. Hh signalling is mediated by its amino-terminal domain (HhN), which is dually lipidated and secreted as part of a multivalent lipoprotein particle. Reception of the HhN signal is modulated by several cell-surface proteins on responding cells, including Patched (Ptc), Smoothened (Smo), Ihog (known as CDO or CDON in mammals) and the vertebrate-specific proteins Hip (also known as Hhip) and Gas1 (ref. 11). Drosophila Ihog and its vertebrate homologues CDO and BOC contain multiple immunoglobulin and fibronectin type III (FNIII) repeats, and the first FNIII repeat of Ihog binds Drosophila HhN in a heparin-dependent manner. Surprisingly, pull-down experiments suggest that a mammalian Sonic hedgehog N-terminal domain (ShhN) binds a non-orthologous FNIII repeat of CDO. Here we report biochemical, biophysical and X-ray structural studies of a complex between ShhN and the third FNIII repeat of CDO. We show that the ShhN-CDO interaction is completely unlike the HhN-Ihog interaction and requires calcium, which binds at a previously undetected site on ShhN. This site is conserved in nearly all Hh proteins and is a hotspot for mediating interactions between ShhN and CDO, Ptc, Hip and Gas1. Mutations in vertebrate Hh proteins causing holoprosencephaly and brachydactyly type A1 map to this calcium-binding site and disrupt interactions with these partners.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679680/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679680/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McLellan, Jason S -- Zheng, Xiaoyan -- Hauk, Glenn -- Ghirlando, Rodolfo -- Beachy, Philip A -- Leahy, Daniel J -- R01 HD055545/HD/NICHD NIH HHS/ -- Z99 DK999999/Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Oct 16;455(7215):979-83. doi: 10.1038/nature07358. Epub 2008 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18794898" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; Binding Sites ; Calcium/metabolism ; Cell Adhesion Molecules/chemistry/metabolism ; Cell Cycle Proteins/chemistry/metabolism ; Cell Line ; *Conserved Sequence ; Crystallography, X-Ray ; Drosophila Proteins/*chemistry/*metabolism ; Drosophila melanogaster/chemistry ; Fibronectins/chemistry ; GPI-Linked Proteins ; Hedgehog Proteins/*chemistry/genetics/*metabolism ; Humans ; Immunoglobulin G/chemistry/metabolism ; Membrane Glycoproteins/*chemistry/*metabolism ; Membrane Proteins/chemistry/metabolism ; Mice ; Models, Molecular ; Protein Binding/genetics ; Protein Structure, Tertiary ; Receptors, Cell Surface/*chemistry/*metabolism ; *Sequence Homology, Amino Acid ; Signal Transduction ; Tumor Suppressor Proteins/chemistry/metabolism

Print ISSN: 0028-0836

Electronic ISSN: 1476-4687

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics

Published by Nature Publishing Group (NPG)

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Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor (2010)

B. P. Barnett ; Y. Hwang ; M. S. Taylor ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 330(6011): 1689-92. doi: 10.1126/science.1196154.

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Publication Date: 2010-11-26

Description: Ghrelin is a gastric peptide hormone that stimulates weight gain in vertebrates. The biological activities of ghrelin require octanoylation of the peptide on Ser(3), an unusual posttranslational modification that is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). Here, we describe the design, synthesis, and characterization of GO-CoA-Tat, a peptide-based bisubstrate analog that antagonizes GOAT. GO-CoA-Tat potently inhibits GOAT in vitro, in cultured cells, and in mice. Intraperitoneal administration of GO-CoA-Tat improves glucose tolerance and reduces weight gain in wild-type mice but not in ghrelin-deficient mice, supporting the concept that its beneficial metabolic effects are due specifically to GOAT inhibition. In addition to serving as a research tool for mapping ghrelin actions, GO-CoA-Tat may help pave the way for clinical targeting of GOAT in metabolic diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068526/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068526/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barnett, Brad P -- Hwang, Yousang -- Taylor, Martin S -- Kirchner, Henriette -- Pfluger, Paul T -- Bernard, Vincent -- Lin, Yu-yi -- Bowers, Erin M -- Mukherjee, Chandrani -- Song, Woo-Jin -- Longo, Patti A -- Leahy, Daniel J -- Hussain, Mehboob A -- Tschop, Matthias H -- Boeke, Jef D -- Cole, Philip A -- P01 CA016519/CA/NCI NIH HHS/ -- P01 CA016519-35/CA/NCI NIH HHS/ -- P30 DK079637/DK/NIDDK NIH HHS/ -- P60 DK079637/DK/NIDDK NIH HHS/ -- P60 DK079637-05/DK/NIDDK NIH HHS/ -- R01 DK081472/DK/NIDDK NIH HHS/ -- R01 DK081472-01A1/DK/NIDDK NIH HHS/ -- R01 DK081472-02/DK/NIDDK NIH HHS/ -- R01 DK081472-03/DK/NIDDK NIH HHS/ -- R01 GM062437/GM/NIGMS NIH HHS/ -- R01 GM062437-04/GM/NIGMS NIH HHS/ -- R01 GM062437-11/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2010 Dec 17;330(6011):1689-92. doi: 10.1126/science.1196154. Epub 2010 Nov 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21097901" target="_blank"〉PubMed〈/a〉

Keywords: Acylation ; Acyltransferases/*antagonists & inhibitors ; Animals ; Cell Survival/drug effects ; Drug Design ; Enzyme Inhibitors/chemical synthesis/*pharmacology/toxicity ; Ghrelin/deficiency/genetics/*metabolism ; Glucose/*metabolism ; Glucose Tolerance Test ; HeLa Cells ; Homeostasis ; Humans ; Insulin/metabolism ; Ion Channels/metabolism ; Islets of Langerhans/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondrial Proteins/metabolism ; Peptides/chemical synthesis/*pharmacology/toxicity ; Weight Gain/*drug effects

Print ISSN: 0036-8075

Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

Published by American Association for the Advancement of Science (AAAS)

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Structure of the extracellular region of HER3 reveals an interdomain tether (2002)

H. S. Cho ; D. J. Leahy

American Association for the Advancement of Science (AAAS)

In: Science. 297(5585): 1330-3. doi: 10.1126/science.1074611.

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Publication Date: 2002-08-03

Description: We have determined the 2.6 angstrom crystal structure of the entire extracellular region of human HER3 (ErbB3), a member of the epidermal growth factor receptor (EGFR) family. The structure consists of four domains with structural homology to domains found in the type I insulin-like growth factor receptor. The HER3 structure reveals a contact between domains II and IV that constrains the relative orientations of ligand-binding domains and provides a structural basis for understanding both multiple-affinity forms of EGFRs and conformational changes induced in the receptor by ligand binding during signaling. These results also suggest new therapeutic approaches to modulating the behavior of members of the EGFR family.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cho, Hyun-Soo -- Leahy, Daniel J -- New York, N.Y. -- Science. 2002 Aug 23;297(5585):1330-3. Epub 2002 Aug 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biophysical Chemistry, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12154198" target="_blank"〉PubMed〈/a〉

Keywords: Amino Acid Sequence ; Amino Acid Substitution ; Animals ; CHO Cells ; Cricetinae ; Crystallography, X-Ray ; Dimerization ; Epidermal Growth Factor/chemistry/metabolism ; Humans ; Hydrogen Bonding ; Ligands ; Molecular Sequence Data ; Protein Conformation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptor, Epidermal Growth Factor/chemistry/metabolism ; Receptor, ErbB-3/*chemistry/metabolism ; Recombinant Proteins/chemistry ; Signal Transduction

Print ISSN: 0036-8075

Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

Published by American Association for the Advancement of Science (AAAS)

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Structure of a fibronectin type III domain from tenascin phased by MAD analysis of the selenomethionyl protein (1992)

D. J. Leahy ; W. A. Hendrickson ; I. Aukhil ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 258(5084): 987-91.

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Publication Date: 1992-11-06

Description: Fibronectin type III domains are found in many different proteins including cell surface receptors and cell adhesion molecules. The crystal structure of one such domain from the extracellular matrix protein tenascin was determined. The structure was solved by multiwavelength anomalous diffraction (MAD) phasing of the selenomethionyl protein and has been refined to 1.8 angstrom resolution. The folding topology of this domain is identical to that of the extracellular domains of the human growth hormone receptor, the second domain of CD4, and PapD. Although distinct, this topology is similar to that of immunoglobulin constant domains. An Arg-Gly-Asp (RGD) sequence that can function for cell adhesion is found in a tight turn on an exposed loop.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Leahy, D J -- Hendrickson, W A -- Aukhil, I -- Erickson, H P -- CA-47056/CA/NCI NIH HHS/ -- DE-07801/DE/NIDCR NIH HHS/ -- GM-34102/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1992 Nov 6;258(5084):987-91.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1279805" target="_blank"〉PubMed〈/a〉

Keywords: Amino Acid Sequence ; Animals ; Cell Adhesion Molecules, Neuronal/*chemistry ; Chickens ; Crystallization ; Escherichia coli/genetics ; Extracellular Matrix Proteins/*chemistry ; Fibronectins/*chemistry ; Humans ; Immunoglobulin Constant Regions/chemistry ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Sequence Data ; Molecular Structure ; Protein Folding ; Protein Structure, Secondary ; Receptors, Somatotropin/chemistry ; Recombinant Proteins/chemistry ; Tenascin ; *X-Ray Diffraction

Print ISSN: 0036-8075

Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

Published by American Association for the Advancement of Science (AAAS)

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Electronic Resource

Photodissociation dynamics of the N3 radical (1993)

Continetti, R. E. ; Cyr, D. R. ; Osborn, D. L. ; [et al.]

College Park, Md. : American Institute of Physics (AIP)

The Journal of Chemical Physics 99 (1993), S. 2616-2631

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ISSN: 1089-7690

Source: AIP Digital Archive

Topics: Physics , Chemistry and Pharmacology

Notes: The dissociation dynamics of the B˜ 2Σu+ state of N3 were investigated using fast radical beam photodissociation coupled with a new coincidence wedge-and-strip-anode particle detector. With this detector, detailed photofragment kinetic energy and angular distributions can be measured as a function of excitation energy. Calibration of the detector by studies of the predissociation of the O2 B 3Σu− state is discussed. Methods of extracting the center-of-mass kinetic energy and angular distributions are presented. The photodissociation results for N3 show that from the vibrationless level of the B˜ 2Σu+ state in N3, both spin-allowed [N3→N(2D)+N2(1Σg+)] and spin-forbidden [N3→N(4S)+N2(1Σg+)] dissociation processes occur. Bend excitation in the B˜ 2Σu+ state, however, enhances the spin-allowed dissociation process considerably. The kinetic energy distributions reveal partially resolved vibrational structure in the N2 fragment, and indicate substantial rotational excitation of the N2. This implies that bent geometries play a major role in the dissociation of the N3 B˜ state. Possible mechanisms for the spin-forbidden and spin-allowed dissociation channels are discussed.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1063/1.465224

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Electronic Resource

Fast beam photodissociation of the CH2NO2 radical (1993)

Cyr, D. R. ; Leahy, D. J. ; Osborn, D. L. ; [et al.]

College Park, Md. : American Institute of Physics (AIP)

The Journal of Chemical Physics 99 (1993), S. 8751-8764

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ISSN: 1089-7690

Source: AIP Digital Archive

Topics: Physics , Chemistry and Pharmacology

Notes: The photodissociation of the nitromethyl radical, CH2NO2, has been studied using a fast beam photofragment translational spectrometer. In these experiments, a fast beam of mass selected, internally cold nitromethyl radicals is formed via negative ion photodetachment of CH2NO−2 and subsequently dissociated. The recoiling photofragments are detected in coincidence using a microchannel plate detector equipped with a time- and position-sensing anode. Two dissociation product channels are observed at each of three dissociation wavelengths investigated in the range 240–270 nm and are identified as (I) CH2NO2→CH2NO+O and (II) CH2NO2→H2CO+NO. In marked contrast to the ultraviolet photodissociation of CH3NO2, no evidence is found for simple C–N bond fission to give (III) CH2NO2→CH2+NO2. Translational energy and angular distributions were obtained for the two observed channels. The translational energy distribution of channel (I) peaks at only 5–8 kcal/mol, while the distribution for channel (II) peaks at ∼60 kcal/mol. The angular distributions for both channels are largely isotropic. The nature of the electronic excitation and dissociation dynamics are considered at length. The upper state in the electronic transition is assigned to the 1 2B1 state. Results of attempts to model various aspects of the dissociation dynamics as statistical processes on the ground state surface indicate this mechanism is very unlikely. Instead, both dissociation channels are believed to occur primarily on excited state surfaces, and mechanisms for these processes are proposed.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1063/1.465597

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