Structure and permeation mechanism of a mammalian urea transporter.
As an adaptation to infrequent access to water, terrestrial mammals produce urine that is hyperosmotic to plasma. To prevent osmotic diuresis by the large quantity of urea generated by protein catabolism, the kidney epithelia contain facilitative urea transporters (UTs) that allow rapid equilibration between the urinary space and the hyperosmotic interstitium. Here we report the first X-ray crystal structure of a mammalian UT, UT-B, at a resolution of 2.36 Å. UT-B is a homotrimer and each protomer contains a urea conduction pore with a narrow selectivity filter. Structural analyses and molecular dynamics simulations showed that the selectivity filter has two urea binding sites separated by an approximately 5.0 kcal/mol energy barrier. Functional studies showed that the rate of urea conduction in UT-B is increased by hypoosmotic stress, and that the site of osmoregulation coincides with the location of the energy barrier.
Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Elena J
EJ
Levin
Yu
Y
Cao
Giray
G
Enkavi
Matthias
M
Quick
Yaping
Y
Pan
Emad
E
Tajkhorshid
Ming
M
Zhou
D000818:Animals; D002417:Cattle; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray / Q000379:methods; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008024:Ligands; D008081:Liposomes / Q000737:chemistry; D026901:Membrane Transport Proteins / Q000737:chemistry*; D008660:Metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009995:Osmosis; D011506:Proteins / Q000737:chemistry; D014508:Urea / Q000737:chemistry; D014982:Xenopus laevis; D000096982:Urea Transporters
D008024:Ligands; D008081:Liposomes; D026901:Membrane Transport Proteins; D011506:Proteins; D014508:Urea; D000096982:Urea Transporters