BODIL is a molecular modeling environment geared to help the user to quickly identify key features of proteins critical to molecular recognition, especially (1) in drug discovery applications, and (2) to understand the structural basis for function. The program incorporates state-of-the-art graphics, sequence and structural alignment methods, among other capabilities needed in modern structure-function-drug target research. BODIL has a flexible design that allows on-the-fly incorporation of new modules, has intelligent memory management, and fast multi-view graphics. A beta version of BODIL and an accompanying tutorial are available at http://www.abo.fi/fak/mnf/bkf/research/johnson/bodil.html.

No abstract

Conformational activation increases the affinity of integrins to their ligands. On ligand binding, further changes in integrin conformation elicit cellular signalling. Unlike any of the natural ligands of a2b1 integrin, human echovirus 1 (EV1) seemed to bind more avidly a 'closed' than an activated 'open' form of the a2I domain. Furthermore, a mutation E336A in the a2 subunit, which inactivated a2b1 as a collagen receptor, enhanced a2b1 binding to EV1. Thus, EV1 seems to recognize an inactive integrin, and not even the virus binding could trigger the conformational activation of a2b1. This was supported by the fact that the integrin clustering by EV1 did not activate the p38 MAP kinase pathway, a signalling pathway that was shown to be dependent on E336-related conformational changes in a2b1. Furthermore, the mutation E336A did neither prevent EV1 induced and a2b1 mediated protein kinase C activation nor EV1 internalization. Thus, in its entry strategy EV1 seems to rely on the activation of signalling pathways that are dependent on a2b1 clustering, but do not require the conformational regulation of the receptor.

No abstract

Integrins are cell surface receptors for several microbial pathogens including echovirus 1 (EV1), a picornavirus. Cryo-electron microscopy revealed that the functional domain (␣ 2 I) of human ␣ 2 ␤ 1 integrin binds to a surface depression on the EV1 capsid. This three-dimensional structure of EV1 bound to ␣ 2 I domain provides the first structural details of an integrin interacting with a picornavirus. The model indicates that ␣ 2 ␤ 1 integrin cannot simultaneously bind both EV1 and the physiological ligand collagen. Compared with collagen binding to the ␣ 2 I domain, the virus binds with a 10-fold higher affinity but in vitro uncoating of EV1 was not observed as a result of attachment of ␣ 2 I. A molecular model, constructed on the basis of the EV1-integrin complex, shows that multiple ␣ 2 ␤ 1 heterodimers can bind at adjacent sites around the virus 5-fold symmetry axes without steric hindrance. In agreement with this, virus attachment to ␣ 2 ␤ 1 integrin on the cell surface was found to result in integrin clustering, which can give rise to signaling and facilitate the initiation of the viral entry process that takes place via caveolae-mediated endocytosis.