J Michael Sauder - Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator

Version 1

      Publication Details (including relevant citation   information):

      EMBO J (2004) 23: 282-293.

      Lewis HA, Buchanan SG, Burley SK, Conners K, Dickey M, Dorwart M,   Fowler R, Gao X, Guggino WB, Hendrickson WA, Hunt JF, Kearins MC,   Lorimer D, Maloney PC, Post KW, Rajashankar KR, Rutter ME, Sauder   JM, Shriver S, Thibodeau PH, Thomas PJ, Zhang M, Zhao X, Emtage S


      Cystic fibrosis transmembrane conductance regulator (CFTR) is   an  ATP-binding cassette (ABC) transporter that functions as   a chloride  channel. Nucleotide-binding domain 1 (NBD1), one   of two ABC domains in  CFTR, also contains sites for the   predominant CF-causing mutation and,  potentially, for   regulatory phosphorylation. We have determined crystal    structures for mouse NBD1 in unliganded, ADP- and ATP-bound   states, with  and without phosphorylation. This NBD1 differs   from typical ABC domains  in having added regulatory   segments, a foreshortened subdomain  interconnection, and an   unusual nucleotide conformation. Moreover,  isolated NBD1   has undetectable ATPase activity and its structure is    essentially the same independent of ligand state. Phe508, which   is  commonly deleted in CF, is exposed at a putative   NBD1-transmembrane  interface. Our results are consistent   with a CFTR mechanism, whereby  channel gating occurs   through ATP binding in an NBD1-NBD2 nucleotide  sandwich   that forms upon displacement of NBD1 regulatory segments.

      Address (URL): http://www.nature.com/emboj/journal/v23/n2/abs/7600040a.html