The cryo-electron microscopy structure of γ-Secretase: towards complex assembly, substrate recognition and a catalytic mechanism.

the disease consequences of GLUT1 mutants. Beyond the biological impact, the structure determination not only gets high scores for artistic quality but also represents a significant degree of technical difficulty; success was not the result of luck but rather required inspired experimental design and hard work. What is next? With the structure of the inward facing conformation solved, the next challenge will be to trap and structurally characterizeGLUT1 in other mechanistically relevant states (outward facing, occluded) and in the presence of substrates. Although GLUT1 is a uniporter, the transport kinetics are nontrivial and beg a molecular interpretation [2]. Building on this knowledge, therapeutics may be developed to regulate the function of GLUT1 in response to mutation and cancer. Realizing these long-term goals will require a significant amount of glucose-fueled brain power, but the crucial first step has been brilliantly taken by Yan and co-workers.