On the specificity of heparin/heparan sulfate binding to proteins. Anion-binding sites on antithrombin and thrombin are fundamentally different. PLoS One 2012;7(11):e48632
Date
11/16/2012Pubmed ID
23152789Pubmed Central ID
PMC3495972DOI
10.1371/journal.pone.0048632Scopus ID
2-s2.0-84869073602 (requires institutional sign-in at Scopus site) 43 CitationsAbstract
BACKGROUND: The antithrombin-heparin/heparan sulfate (H/HS) and thrombin-H/HS interactions are recognized as prototypic specific and non-specific glycosaminoglycan (GAG)-protein interactions, respectively. The fundamental structural basis for the origin of specificity, or lack thereof, in these interactions remains unclear. The availability of multiple co-crystal structures facilitates a structural analysis that challenges the long-held belief that the GAG binding sites in antithrombin and thrombin are essentially similar with high solvent exposure and shallow surface characteristics.
METHODOLOGY: Analyses of solvent accessibility and exposed surface areas, gyrational mobility, symmetry, cavity shape/size, conserved water molecules and crystallographic parameters were performed for 12 X-ray structures, which include 12 thrombin and 16 antithrombin chains. Novel calculations are described for gyrational mobility and prediction of water loci and conservation.
RESULTS: The solvent accessibilities and gyrational mobilities of arginines and lysines in the binding sites of the two proteins reveal sharp contrasts. The distribution of positive charges shows considerable asymmetry in antithrombin, but substantial symmetry for thrombin. Cavity analyses suggest the presence of a reasonably sized bifurcated cavity in antithrombin that facilitates a firm 'hand-shake' with H/HS, but with thrombin, a weaker 'high-five'. Tightly bound water molecules were predicted to be localized in the pentasaccharide binding pocket of antithrombin, but absent in thrombin. Together, these differences in the binding sites explain the major H/HS recognition characteristics of the two prototypic proteins, thus affording an explanation of the specificity of binding. This provides a foundation for understanding specificity of interaction at an atomic level, which will greatly aid the design of natural or synthetic H/HS sequences that target proteins in a specific manner.
Author List
Mosier PD, Krishnasamy C, Kellogg GE, Desai URAuthor
Philip Mosier PhD Assistant Professor in the School of Pharmacy Administration department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino AcidsAntithrombins
Binding Sites
Heparin
Heparitin Sulfate
Molecular Docking Simulation
Protein Binding
Protein Conformation
Proteins
Species Specificity
Thrombin
Water
