Structural identification of the pathway of long-range communication in an allosteric enzyme.
Allostery is a common mechanism of regulation of enzyme activity and specificity, and its signatures are readily identified from functional studies. For many allosteric systems, structural evidence exists of long-range communication among protein domains, but rarely has this communication been traced to a detailed pathway. The thrombin mutant D102N is stabilized in a self-inhibited conformation where access to the active site is occluded by a collapse of the entire 215-219 beta-strand. Binding of a fragment of the protease activated receptor PAR1 to exosite I, 30-A away from the active site region, causes a large conformational change that corrects the position of the 215-219 beta-strand and restores access to the active site. The crystal structure of the thrombin-PAR1 complex, solved at 2.2-A resolution, reveals the details of this long-range allosteric communication in terms of a network of polar interactions.
Gandhi
Prafull S
PS
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Box 8231, St. Louis, MO 63110, USA.
Chen
Zhiwei
Z
Mathews
F Scott
FS
Di Cera
Enrico
E
D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011487:Protein Conformation; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D044463:Receptor, PAR-1; D013917:Thrombin