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Targeted molecular dynamics reveals overall common conformational changes upon hybrid domain swing‐out in β3 integrins
Author(s) -
Provasi Davide,
Murcia Marta,
Coller Barry S.,
Filizola Marta
Publication year - 2009
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.22463
Subject(s) - allosteric regulation , integrin , biophysics , helix (gastropod) , molecular dynamics , conformational change , chemistry , transition (genetics) , turn (biochemistry) , loop (graph theory) , receptor , crystallography , stereochemistry , biology , biochemistry , ecology , computational chemistry , snail , gene , mathematics , combinatorics
The β3 integrin family members αIIβ3 and αVβ3 signal bidirectionally through long‐range allosteric changes, including a transition from a bent unliganded‐closed low‐affinity state to an extended liganded‐open high‐affinity state. To obtain an atomic‐level description of this transition in an explicit solvent, we carried out targeted molecular dynamics simulations of the headpieces of αIIβ3 and αVβ3 integrins. Although minor differences were observed between these receptors, our results suggest a common transition pathway in which the hybrid domain swing‐out is accompanied by conformational changes within the β3 βA (I‐like) domain that propagate through the α7 helix C‐terminus, and are followed by the α7 helix downward motion and the opening of the β6‐α7 loop. Breaking of contact interactions between the β6‐α7 loop and the α1 helix N‐terminus results in helix straightening, internal rearrangements of the specificity determining loop (SDL), movement of the β1‐α1 loop toward the metal ion dependent adhesion site (MIDAS), and final changes at the interfaces between the β3 βA (I‐like) domain and either the hybrid or the α β‐propeller domains. Taken together, our results suggest novel testable hypotheses of intradomain and interdomain interactions responsible for β3 integrin activation. Proteins 2009. © 2009 Wiley‐Liss, Inc.