期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 28, 页码 11343-11348出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1301079110
关键词
membrane transporter; molecular dynamics simulation; X-ray crystallography
资金
- Japan Society for the Promotion of Science through its Funding Program for World-Leading Innovative R& D on Science and Technology Program
- Core Research for Evolutional Science and Technology Program
- Basic Medical Technologies to Clarify and Control the Mechanisms Underlying Chronic Inflammation
- Japan Science and Technology Agency
- Ministry of Education, Culture, Sports, Science, and Technology [24227004, 22687007]
- High Performance Computing Infrastructure (HPCI)
- Strategic Program Computational Life Science and Application in Drug Discovery and Medical Development
- Ministry of Education, Culture, Sports, Science, and Technology
- Medical Research Council Career Development Award [G0900399]
- Wellcome Trust Structural Biology DPhil studentship
- MRC [G0900399] Funding Source: UKRI
- Medical Research Council [G0900399] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [25104009, 22247024, 22117007, 24121704, 24687016] Funding Source: KAKEN
Proton-dependent oligopeptide transporters (POTs) are major facilitator superfamily (MFS) proteins that mediate the uptake of peptides and peptide-like molecules, using the inwardly directed H+ gradient across the membrane. The human POT family transporter peptide transporter 1 is present in the brush border membrane of the small intestine and is involved in the uptake of nutrient peptides and drug molecules such as beta-lactam antibiotics. Although previous studies have provided insight into the overall structure of the POT family transporters, the question of how transport is coupled to both peptide and H+ binding remains unanswered. Here we report the high-resolution crystal structures of a bacterial POT family transporter, including its complex with a dipeptide analog, alafosfalin. These structures revealed the key mechanistic and functional roles for a conserved glutamate residue (Glu310) in the peptide binding site. Integrated structural, biochemical, and computational analyses suggested a mechanism for H+-coupled peptide symport in which protonated Glu310 first binds the carboxyl group of the peptide substrate. The deprotonation of Glu310 in the inward open state triggers the release of the bound peptide toward the intracellular space and salt bridge formation between Glu310 and Arg43 to induce the state transition to the occluded conformation.
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