All-Atom Structural Models for Complexes of Insulin-Like Growth Factors IGF1 and IGF2 with Their Cognate Receptor
ABSTRACT Type 1 insulin-like growth factor receptor (IGF1R) is a membrane-spanning glycoprotein of the insulin receptor family that has been implicated in a variety of cancers. The key questions related to molecular mechanisms governing ligand recognition by IGF1R remain unanswered, partly due to the lack of testable structural models of apo or ligand-bound receptor complexes. Using a homology model of the IGF1R ectodomain IGF1RDeltabeta, we present the first experimentally consistent all-atom structural models of IGF1/IGF1RDeltabeta and IGF2/IGF1RDeltabeta complexes. Our explicit-solvent molecular dynamics (MD) simulation of apo-IGF1RDeltabeta shows that it displays asymmetric flexibility mechanisms that result in one of two binding pockets accessible to growth factors IGF1 and IGF2, as demonstrated via an MD-assisted Monte Carlo docking procedure. Our MD-generated ensemble of structures of apo and IGF1-bound IGF1RDeltabeta agrees reasonably well with published small-angle X-ray scattering data. We observe simultaneous contacts of each growth factor with sites 1 and 2 of IGF1R, suggesting cross-linking of receptor subunits. Our models provide direct evidence in favor of suggested electrostatic complementarity between the C-domain (IGF1) and the cysteine-rich domain (IGF1R). Our IGF1/IGF1RDeltabeta model provides structural bases for the observation that a single IGF1 molecule binds to IGF1RDeltabeta at low concentrations in small-angle X-ray scattering studies. We also suggest new possible structural bases for differences in the affinities of insulin, IGF1, and IGF2 for their noncognate receptors.
Conference Paper: LFT formulation for multivariate polynomial problems[Show abstract] [Hide abstract]
ABSTRACT: Robust control system analysis and design is based on an uncertainty description, called a linear fractional transformation (LFT), which separates the uncertain (or varying) part of the system from the nominal system. Low-order LFT models are difficult to form for nonlinear parameter-dependent systems. The paper presents a numerical computational method that can be used to construct low-order LFT models for multivariate polynomial and rational problems based on simple matrix computations. This LFT modeling method makes current robust and linear parameter varying (LPV) control analysis and design methods accessible to a broad class of difficult practical problemsAmerican Control Conference, 1998. Proceedings of the 1998; 07/1998
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ABSTRACT: High density mastering is the key technology to manufacture next generation optical disc recording with over 20 GB capacity for more than 2 hours of HDTV digital data. We developed a deep UV laser beam recorder (DUV-LBR) and the related mastering process to achieve such a high density (M. Takeda et al, Jpn. J. Appl. Phys. vol. 38, pp. 1837-1838, 1999), which is now to be introduced in the disc mastering process line of DVR-blue (I. Ichimura et al, Tech. Dig. ODS2001, pp. 139-141, 2001). Beyond DUV-LBR, an electron beam recorder (EBR) was proposed to produce further high density pit patterns (Y. Wada et al, Jpn. J. Appl. Phys. vol. 40, pp. 1653-1660, 2001). We have developed a new concept EBR with a novel differential pumping head attached to the bottom portion of the electron beam column. It has no vacuum chamber and an air-spindle motor with a translation stage under the electron beam column is installed in the atmosphere like a conventional LBR. The differential pumping head effectively separates the high vacuum region and the surrounding atmospheric pressure region. The high vacuum region, which is necessary for the electron beam emitted from the column and focused onto the resist coated silicon (Si) substrate, is confined within only a narrow gap between the head and the resist surface. As the spindle motor and the translation stage are operated not in a vacuum chamber but in the atmosphere, high speed recording with sufficient rotational and translational accuracy can be attained. Furthermore, the main body of the EBR can be very compact and cost effective due to the lack of a large and expensive vacuum chamber. In this paper, we report 25 GB density recording performance of our newly developed EBR and some experimental results of recording and reproducing even higher densities up to 50 GB.Optical Memory and Optical Data Storage Topical Meeting, 2002. International Symposium on; 02/2002
Article: IGF1R mutations as cause of SGA[Show abstract] [Hide abstract]
ABSTRACT: Until 2003 monogenetic aberrations that lead to a child that is born too small for gestational age (SGA) were poorly defined. With the first report of mutations within the insulin-like growth factor type 1 receptor (IGF1R) gene in two non-syndromic patients born SGA, who failed to thrive despite normal or even elevated IGF1 serum concentrations the concept of IGF1 resistance has been established. The identification of additional individuals bearing IGF1R mutations along with comparative, genetic, structural and biochemical studies has provided evidence for the pathogenic impact of the IGF1R mutations on human longitudinal growth. However, the variability in the occurrence of additional clinical manifestations, such as developmental delay, might indicate that the pleiotropic functions of the IGF-IGF1R system are partially redundant. It is apparent that we have just begun to unravel the multifaceted IGF1R actions at the interface of growth control, maintenance of metabolic homeostasis and neurodevelopment and neural protection.Best Practice & Research: Clinical Endocrinology & Metabolism 02/2011; 25(1):191-206. DOI:10.1016/j.beem.2010.09.012