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August 4, 2003
Volume 81, Number 31
CENEAR 81 31 p. 10
ISSN 0009-2347


X-ray structures will allow modeling of whole family of transporter proteins


Scientists have captured high-resolution pictures of two previously elusive members of a family of membrane proteins that pump molecules across cell membranes against their concentration gradients [Science, 301, 610 and 616 (2003)].

The X-ray crystal structures of these two transporters “will serve as models for this very interesting and medically important family of proteins,” comments National Cancer Institute biophysicist Sriram Subramaniam.

Members of the “major facilitator superfamily” manage to move all kinds of cargo “uphill”—including sugars, antibiotics, and peptides—and have been implicated in antibiotic resistance, diabetes, and many other diseases. The membrane proteins power this thermodynamically unfavorable task with the energy harnessed by moving a second molecule down its concentration gradient—that is, from a region of high concentration to low concentration. For the bacterial lactose permease LacY, a proton gradient powers the pumping of lactose. The bacterial transporter GlpT relies on a gradient of inorganic phosphate to drive the transport of glycerol-3-phosphate.

The flexibility shared by members of this protein family has made it difficult to study their structures. After years of trying, the 3.5-Å LacY structure was solved by a team led by Howard Hughes Medical Institute investigator and biochemist H. Ronald Kaback of the University of California, Los Angeles, and crystallographer So Iwata of Imperial College, London. Crystallographer Da-Neng Wang and his coworkers at New York University School of Medicine obtained the 3.3-Å structure of GlpT.

In both structures, a pair of six-helix domains are arranged like the two halves of a clam shell, partially enclosing a solvent-filled crevice that opens into the cytoplasm. The shell’s “hinge” blocks access to the other side of the membrane. In the LacY structure, a lactose homolog is bound in the hydrophilic crevice.

On the basis of the structure and the vast amount of biochemical data Kaback’s lab has collected on LacY, Kaback and Iwata suggest that proton binding causes LacY’s two protein domains to pinch closed, forcing the hinged side open. This would provide a path for lactose to pass to the other side of the membrane. Wang’s team proposes a similar mechanism for GlpT.

The molecular details of how a concentration gradient might be harnessed to power such a conformational change remain unclear, Subramaniam notes. To this end, both teams are working to trap their proteins in the op-posite conformation.

SCIENCE © 2003
PUMPING ACTION The bent and otherwise distorted helices seen in the structures of LacY (left) and GlpT (right) may play an important role in the conformational changes these proteins undergo. (Bound lactose homolog is shown in black.)


Chemical & Engineering News
Copyright © 2003 American Chemical Society

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H. Ronald Kaback

So Iwata

Da-Neng Wang

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