کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
443661 692746 2009 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Investigating the differential activation of vascular endothelial growth factor (VEGF) receptors
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی تئوریک و عملی
پیش نمایش صفحه اول مقاله
Investigating the differential activation of vascular endothelial growth factor (VEGF) receptors
چکیده انگلیسی

The vascular endothelial growth factors are key mediators of angiogenesis and are also related to several physiological processes such as monocyte chemotaxis, dendritic cell development, hematopoietic stem cell survival, and many others. PlGF, VEGF, VEGFB, VEGFC and VEGFD were identified as members of the vascular endothelial growth factor family. They act by differential activation of three receptors: Flt-1, KDR and Flt-4. PlGF and VEGFB only activate Flt-1. VEGF activates both Flt-1 and KDR. VEGFC and VEGFD activate KDR and Flt-4. The available three dimensional structures of VEGF and PlGF, in complex with the domain-2 of Flt-1, show that both proteins bind in a very similar way to Flt-1 receptor. Here we construct the three dimensional model of the domain-2 of KDR receptor using the same domain of Flt-1 as template. We also construct the model complexes VEGF/KDR, VEGFB/Flt-1, VEGFB/KDR and PlGF/KDR. Molecular dynamics simulations with explicit solvent are carried out on eleven molecular systems: unbound VEGF, VEGF/Flt-1D2, VEGF/KDRD2, unbound PlGF, PlGF/Flt-1D2, PlGF/KDRD2, unbound VEGFB, VEGFB/Flt-1D2, VEGFB/KDRD2, unbound Flt-1D2 and unbound KDRD2. We analyze protein–protein interactions, shape complementarity, charge complementarity and hydrogen bonds. As a coarse estimation of the desolvation penalties, we assume a correlation to the number of hydrogen bonds with solvent molecules that are lost upon complex formation. The results herein are consistent with the experimental selectivity profile (VEGF being able to activate both Flt-1 and KDR receptors while VEGFB and PlGF being only able to activate Flt-1), and provide a collection of evidences sustaining the complementarity of polar interactions as the main responsible for protein recognition and selectivity.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular Graphics and Modelling - Volume 28, Issue 3, October 2009, Pages 287–296
نویسندگان
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