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Structural basis for EGFR ligand sequestration by Argos (2008)

D. E. Klein ; S. E. Stayrook ; F. Shi ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 453(7199): 1271-5. doi: 10.1038/nature06978.

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Publication Date: 2008-05-27

Description: Members of the epidermal growth factor receptor (EGFR) or ErbB/HER family and their activating ligands are essential regulators of diverse developmental processes. Inappropriate activation of these receptors is a key feature of many human cancers, and its reversal is an important clinical goal. A natural secreted antagonist of EGFR signalling, called Argos, was identified in Drosophila. We showed previously that Argos functions by directly binding (and sequestering) growth factor ligands that activate EGFR. Here we describe the 1.6-A resolution crystal structure of Argos bound to an EGFR ligand. Contrary to expectations, Argos contains no EGF-like domain. Instead, a trio of closely related domains (resembling a three-finger toxin fold) form a clamp-like structure around the bound EGF ligand. Although structurally unrelated to the receptor, Argos mimics EGFR by using a bipartite binding surface to entrap EGF. The individual Argos domains share unexpected structural similarities with the extracellular ligand-binding regions of transforming growth factor-beta family receptors. The three-domain clamp of Argos also resembles the urokinase-type plasminogen activator (uPA) receptor, which uses a similar mechanism to engulf the EGF-like module of uPA. Our results indicate that undiscovered mammalian counterparts of Argos may exist among other poorly characterized structural homologues. In addition, the structures presented here define requirements for the design of artificial EGF-sequestering proteins that would be valuable anti-cancer therapeutics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526102/" 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/PMC2526102/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Klein, Daryl E -- Stayrook, Steven E -- Shi, Fumin -- Narayan, Kartik -- Lemmon, Mark A -- R01 CA079992/CA/NCI NIH HHS/ -- R01 CA079992-10/CA/NCI NIH HHS/ -- R01 CA125432/CA/NCI NIH HHS/ -- R01 CA125432-01A1/CA/NCI NIH HHS/ -- England -- Nature. 2008 Jun 26;453(7199):1271-5. doi: 10.1038/nature06978. Epub 2008 May 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18500331" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; Binding Sites ; Cell Line ; Crystallography, X-Ray ; Drosophila Proteins/*chemistry/*metabolism ; Drosophila melanogaster/*chemistry/cytology ; Epidermal Growth Factor/*chemistry/*metabolism ; Eye Proteins/*chemistry/*metabolism ; Humans ; Ligands ; Membrane Proteins/*chemistry/*metabolism ; Models, Molecular ; Nerve Tissue Proteins/*chemistry/*metabolism ; Protein Structure, Tertiary ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/chemistry/*metabolism ; Receptors, Transforming Growth Factor beta/chemistry/metabolism ; Spodoptera

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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ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor (2009)

D. Alvarado ; D. E. Klein ; M. A. Lemmon

Nature Publishing Group (NPG)

In: Nature. 461(7261): 287-91. doi: 10.1038/nature08297.

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Publication Date: 2009-09-01

Description: The orphan receptor tyrosine kinase ErbB2 (also known as HER2 or Neu) transforms cells when overexpressed, and it is an important therapeutic target in human cancer. Structural studies have suggested that the oncogenic (and ligand-independent) signalling properties of ErbB2 result from the absence of a key intramolecular 'tether' in the extracellular region that autoinhibits other human ErbB receptors, including the epidermal growth factor (EGF) receptor. Although ErbB2 is unique among the four human ErbB receptors, here we show that it is the closest structural relative of the single EGF receptor family member in Drosophila melanogaster (dEGFR). Genetic and biochemical data show that dEGFR is tightly regulated by growth factor ligands, yet a crystal structure shows that it, too, lacks the intramolecular tether seen in human EGFR, ErbB3 and ErbB4. Instead, a distinct set of autoinhibitory interdomain interactions hold unliganded dEGFR in an inactive state. All of these interactions are maintained (and even extended) in ErbB2, arguing against the suggestion that ErbB2 lacks autoinhibition. We therefore suggest that normal and pathogenic ErbB2 signalling may be regulated by ligands in the same way as dEGFR. Our findings have important implications for ErbB2 regulation in human cancer, and for developing therapeutic approaches that target novel aspects of this orphan receptor.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762480/" 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/PMC2762480/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alvarado, Diego -- Klein, Daryl E -- Lemmon, Mark A -- R01 CA079992/CA/NCI NIH HHS/ -- R01 CA079992-09/CA/NCI NIH HHS/ -- R01 CA079992-10/CA/NCI NIH HHS/ -- R01 CA125432/CA/NCI NIH HHS/ -- R01 CA125432-01A1/CA/NCI NIH HHS/ -- R01 CA125432-02/CA/NCI NIH HHS/ -- R01 CA125432-03/CA/NCI NIH HHS/ -- England -- Nature. 2009 Sep 10;461(7261):287-91. doi: 10.1038/nature08297. Epub 2009 Aug 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19718021" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; Cell Line ; Crystallography, X-Ray ; Drosophila Proteins/*antagonists & inhibitors/chemistry/genetics/*metabolism ; Drosophila melanogaster/chemistry/*metabolism ; Enzyme Activation ; Humans ; Ligands ; Models, Molecular ; Protein Structure, Tertiary ; Receptor, Epidermal Growth Factor/*antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Receptor, ErbB-2/antagonists & inhibitors/*chemistry/*metabolism ; Receptors, Invertebrate Peptide/*antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Scattering, Small Angle ; Solubility ; X-Ray Diffraction

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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Characterization of the effects of continuous salt processing on the performance of molten salt fusion breeder blankets (1985)

Patterson-Hine, F. A. ; Davidson, J. W. ; Klein, D. E. ; [et al.]

Springer

Journal of fusion energy 4 (1985), S. 375-388

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ISSN: 1572-9591

Keywords: fusion breeder ; molten salt blanket ; molten salt processing

Source: Springer Online Journal Archives 1860-2000

Topics: Energy, Environment Protection, Nuclear Power Engineering

Notes: Abstract Several continuous salt processing options are available for use in molten salt fusion breeder blanket designs: fluorination only, fluorination plus reductive extraction, and fluorination, plus reductive extraction, plus metal transfer. The effects of processing on blanket performance have been assessed for these three levels of processing and various equilibrium uranium concentrations in the salt. A one-dimensional model of the blanket was used in the neutronics analysis, which incorporated transport calculations with time-dependent isotope generation and depletion calculations. The method of salt processing was found to have little affect on the level of radioactivity, toxicity, or the thermal behavior of the salt during operation of the reactor. The processing rates necessary to maintain the desired uranium concentrations in the suppressed-fission environment were quite low, which permitted only long-lived species to be removed from the salt. The effects of the processing therefore became apparent only after the radioactivity due to the short-lived species diminished. The effects of the additional processing (reductive extraction and metal transfer) could be seen after approximately 1 year of decay, but were not significant at times closer to shutdown. The reduced radioactivity and corresponding heat deposition were thus of no consequence in accident or maintenance situations. Net fissile production in the Be/MS blanket concept at a fusion power level of 3000 MW at 70% capacity ranged from 5100 kg/year to 5170 kg/year for uranium concentrations of 0.11% and 1.0%233U in thorium, respectively, with fluorination-only processing. The addition of processing by reductive extraction resulted in 5125 kg/year for the 0.11%233U case and 5225 kg/year for the 1.0%233U case.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF01082702

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Determination of trace element impurities in aspirin tablets by neutron activation analysis (1986)

Iskander, F. Y. ; Klein, D. E. ; Bauer, T. L.

Springer

Journal of radioanalytical and nuclear chemistry 97 (1986), S. 353-357

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ISSN: 1588-2780

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Energy, Environment Protection, Nuclear Power Engineering

Notes: Abstract Twenty five trace and minor elements (aluminium, arsenic, barium, bromine, cerium, chlorine, cobalt, chromium, cesium, europium, iron, hafnium, potassium, magnesium, manganese, sodium, rubidium, antimony, scandium, selenium, strontium, thorium, titanium, vanadium and zinc) in five different Egyptian aspirin brands (Aspo, Askin, Aspocid, Aspeol and Rivo) have been determined by instrumental neutron activation analysis. It has been concluded that the concentration of arsenic, barium, bromine, cobalt, chromium, iron (except in Aspocid), magnesium, manganese, rubidium, selenium, strontium and zinc in the Egyptian brands is below or within the concentration range reported for these elements in 16 American aspirin and aspirin-like brands.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF02035681

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Finite element simulation of recirculating flows with heat transfer (1987)

Polansky, G. F. ; Lamb, J. P. ; Klein, D. E.

New York, NY [u.a.] : Wiley-Blackwell

Communications in Applied Numerical Methods 3 (1987), S. 17-22

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ISSN: 0748-8025

Keywords: Engineering ; Engineering General

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Mathematics , Technology

Notes: The finite element method was investigated as a means of simulating incompressible laminar and turbulent flow with heat transfer. Governing equations include the complete, two-dimensional Navier-Stokes equations expressed in terms of primitive variables. The turbulent viscosity is determined by a two-equation (k-∊) model of turbulence. Both high Reynolds' number and low Reynolds' number forms of the two-equations model were considered. The formulation was first tested in laminar recirculating flows as well as in a fully developed turbulent channel flow. The code was then applied successfully to flow past a confined backward facing step and to a backward facing ramp. Although the high Reynolds' number turbulence model was found to be incompatible with the current numerical scheme, good results were obtained using the low Reynolds' number model. Results of the current calculations are compared with experimental data and a variety of other computational results.

Additional Material: 3 Ill.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1002/cnm.1630030105

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