The objective of the study was to generate a full-length model for the heteropentameric structure of human alpha 4 beta 2 nicotinic receptor. The monomers structure was derived using a fragmental approach and the pentamer was assembled by protein-protein docking. The reliability of the model was assessed docking a representative set of known nicotinic ligands. Docking results unveiled that the ligand affinity depends on key interactions that the ligand's charged moiety realizes with conserved apolar residues of alpha 4 monomer, whereas the H-bond acceptor group interacts with a less conserved and more heterogeneous subpocket, involving polar residues of beta 2 subunit. The consistency of docking results and the agreement with the experimental data afford an encouraging validation for the proposed model and emphasize the soundness of such a fragmental approach to model any transmembrane protein. (c) 2008 Elsevier Inc. All rights reserved.