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Structural basis for polyspecificity in the POT family of proton-coupled oligopeptide transporters.

Lyons JA, Parker JL, Solcan N, Brinth A, Li D, Shah ST, Caffrey M, Newstead S
EMBO Rep 15 886-93 (2014)
Related entries: 4d2b, 4d2c

Cited: 52 times
EuropePMC logo PMID: 24916388

Abstract

An enigma in the field of peptide transport is the structural basis for ligand promiscuity, as exemplified by PepT1, the mammalian plasma membrane peptide transporter. Here, we present crystal structures of di- and tripeptide-bound complexes of a bacterial homologue of PepT1, which reveal at least two mechanisms for peptide recognition that operate within a single, centrally located binding site. The dipeptide was orientated laterally in the binding site, whereas the tripeptide revealed an alternative vertical binding mode. The co-crystal structures combined with functional studies reveal that biochemically distinct peptide-binding sites likely operate within the POT/PTR family of proton-coupled symporters and suggest that transport promiscuity has arisen in part through the ability of the binding site to accommodate peptides in multiple orientations for transport.

Reviews - 4d2d mentioned but not cited (3)

  1. A comprehensive review of the lipid cubic phase or in meso method for crystallizing membrane and soluble proteins and complexes. Caffrey M. Acta Crystallogr F Struct Biol Commun 71 3-18 (2015)
  2. Recent advances in understanding proton coupled peptide transport via the POT family. Newstead S. Curr Opin Struct Biol 45 17-24 (2017)
  3. Recent advances in understanding prodrug transport through the SLC15 family of proton-coupled transporters. Minhas GS, Newstead S. Biochem Soc Trans 48 337-346 (2020)

Articles - 4d2d mentioned but not cited (10)

  1. Structural basis for polyspecificity in the POT family of proton-coupled oligopeptide transporters. Lyons JA, Parker JL, Solcan N, Brinth A, Li D, Shah ST, Caffrey M, Newstead S. EMBO Rep 15 886-893 (2014)
  2. Multispecific Substrate Recognition in a Proton-Dependent Oligopeptide Transporter. Martinez Molledo M, Quistgaard EM, Flayhan A, Pieprzyk J, Löw C. Structure 26 467-476.e4 (2018)
  3. Structural basis for prodrug recognition by the SLC15 family of proton-coupled peptide transporters. Minhas GS, Newstead S. Proc Natl Acad Sci U S A 116 804-809 (2019)
  4. Structural basis of malodour precursor transport in the human axilla. Minhas GS, Bawdon D, Herman R, Rudden M, Stone AP, James AG, Thomas GH, Newstead S. Elife 7 e34995 (2018)
  5. Cryo-EM structure of PepT2 reveals structural basis for proton-coupled peptide and prodrug transport in mammals. Parker JL, Deme JC, Wu Z, Kuteyi G, Huo J, Owens RJ, Biggin PC, Lea SM, Newstead S. Sci Adv 7 eabh3355 (2021)
  6. Accurate Prediction of Ligand Affinities for a Proton-Dependent Oligopeptide Transporter. Samsudin F, Parker JL, Sansom MSP, Newstead S, Fowler PW. Cell Chem Biol 23 299-309 (2016)
  7. Chemical Modulation of the Human Oligopeptide Transporter 1, hPepT1. Colas C, Masuda M, Sugio K, Miyauchi S, Hu Y, Smith DE, Schlessinger A. Mol Pharm 14 4685-4693 (2017)
  8. Tripeptide binding in a proton-dependent oligopeptide transporter. Martinez Molledo M, Quistgaard EM, Löw C. FEBS Lett 592 3239-3247 (2018)
  9. Computing Substrate Selectivity in a Peptide Transporter. Colas C, Smith DE, Schlessinger A. Cell Chem Biol 23 211-213 (2016)
  10. Structural Insights into the Substrate Transport Mechanisms in GTR Transporters through Ensemble Docking. Peña-Varas C, Kanstrup C, Vergara-Jaque A, González-Avendaño M, Crocoll C, Mirza O, Dreyer I, Nour-Eldin H, Ramírez D. Int J Mol Sci 23 1595 (2022)


Reviews citing this publication (7)

  1. Shared Molecular Mechanisms of Membrane Transporters. Drew D, Boudker O. Annu Rev Biochem 85 543-572 (2016)
  2. Understanding transport by the major facilitator superfamily (MFS): structures pave the way. Quistgaard EM, Löw C, Guettou F, Nordlund P. Nat Rev Mol Cell Biol 17 123-132 (2016)
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  5. Biochemical studies on the structure-function relationship of major drug transporters in the ATP-binding cassette family and solute carrier family. Hong M. Adv Drug Deliv Rev 116 3-20 (2017)
  6. Transporter-Mediated Drug Delivery. Gyimesi G, Hediger MA. Molecules 28 1151 (2023)
  7. Molecular Insights to the Structure-Interaction Relationships of Human Proton-Coupled Oligopeptide Transporters (PepTs). Luo Y, Gao J, Jiang X, Zhu L, Zhou QT, Murray M, Li J, Zhou F. Pharmaceutics 15 2517 (2023)

Articles citing this publication (32)

  1. Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS). Drew D, North RA, Nagarathinam K, Tanabe M. Chem Rev 121 5289-5335 (2021)
  2. Structural biology of solute carrier (SLC) membrane transport proteins. Bai X, Moraes TF, Reithmeier RAF. Mol Membr Biol 34 1-32 (2017)
  3. Human transporters, PEPT1/2, facilitate melatonin transportation into mitochondria of cancer cells: An implication of the therapeutic potential. Huo X, Wang C, Yu Z, Peng Y, Wang S, Feng S, Zhang S, Tian X, Sun C, Liu K, Deng S, Ma X. J Pineal Res 62 (2017)
  4. Gating topology of the proton-coupled oligopeptide symporters. Fowler PW, Orwick-Rydmark M, Radestock S, Solcan N, Dijkman PM, Lyons JA, Kwok J, Caffrey M, Watts A, Forrest LR, Newstead S. Structure 23 290-301 (2015)
  5. Origin and evolution of transporter substrate specificity within the NPF family. Jørgensen ME, Xu D, Crocoll C, Ernst HA, Ramírez D, Motawia MS, Olsen CE, Mirza O, Nour-Eldin HH, Halkier BA. Elife 6 e19466 (2017)
  6. Proton movement and coupling in the POT family of peptide transporters. Parker JL, Li C, Brinth A, Wang Z, Vogeley L, Solcan N, Ledderboge-Vucinic G, Swanson JMJ, Caffrey M, Voth GA, Newstead S. Proc Natl Acad Sci U S A 114 13182-13187 (2017)
  7. Comparative Genomics Analysis of Streptomyces Species Reveals Their Adaptation to the Marine Environment and Their Diversity at the Genomic Level. Tian X, Zhang Z, Yang T, Chen M, Li J, Chen F, Yang J, Li W, Zhang B, Zhang Z, Wu J, Zhang C, Long L, Xiao J. Front Microbiol 7 998 (2016)
  8. Role of electrostatic interactions for ligand recognition and specificity of peptide transporters. Boggavarapu R, Jeckelmann JM, Harder D, Ucurum Z, Fotiadis D. BMC Biol 13 58 (2015)
  9. Thermodynamic evidence for a dual transport mechanism in a POT peptide transporter. Parker JL, Mindell JA, Newstead S. Elife 3 e04273 (2014)
  10. Structural snapshots of human PepT1 and PepT2 reveal mechanistic insights into substrate and drug transport across epithelial membranes. Killer M, Wald J, Pieprzyk J, Marlovits TC, Löw C. Sci Adv 7 eabk3259 (2021)
  11. Crystal Structures of the Extracellular Domain from PepT1 and PepT2 Provide Novel Insights into Mammalian Peptide Transport. Beale JH, Parker JL, Samsudin F, Barrett AL, Senan A, Bird LE, Scott D, Owens RJ, Sansom MSP, Tucker SJ, Meredith D, Fowler PW, Newstead S. Structure 23 1889-1899 (2015)
  12. New natural amino acid-bearing prodrugs boost pterostilbene's oral pharmacokinetic and distribution profile. Azzolini M, Mattarei A, La Spina M, Fanin M, Chiodarelli G, Romio M, Zoratti M, Paradisi C, Biasutto L. Eur J Pharm Biopharm 115 149-158 (2017)
  13. Structure determination of a major facilitator peptide transporter: Inward facing PepTSt from Streptococcus thermophilus crystallized in space group P3121. Quistgaard EM, Martinez Molledo M, Löw C. PLoS One 12 e0173126 (2017)
  14. The cubicon method for concentrating membrane proteins in the cubic mesophase. Ma P, Weichert D, Aleksandrov LA, Jensen TJ, Riordan JR, Liu X, Kobilka BK, Caffrey M. Nat Protoc 12 1745-1762 (2017)
  15. Free Energy Landscape of the Complete Transport Cycle in a Key Bacterial Transporter. Selvam B, Mittal S, Shukla D. ACS Cent Sci 4 1146-1154 (2018)
  16. In situ serial crystallography for rapid de novo membrane protein structure determination. Huang CY, Olieric V, Howe N, Warshamanage R, Weinert T, Panepucci E, Vogeley L, Basu S, Diederichs K, Caffrey M, Wang M. Commun Biol 1 124 (2018)
  17. Salt Bridge Swapping in the EXXERFXYY Motif of Proton-coupled Oligopeptide Transporters. Aduri NG, Prabhala BK, Ernst HA, Jørgensen FS, Olsen L, Mirza O. J Biol Chem 290 29931-29940 (2015)
  18. Genome Mining of Plant NPFs Reveals Varying Conservation of Signature Motifs Associated With the Mechanism of Transport. Longo A, Miles NW, Dickstein R. Front Plant Sci 9 1668 (2018)
  19. Membrane Chemistry Tunes the Structure of a Peptide Transporter. Lasitza-Male T, Bartels K, Jungwirth J, Wiggers F, Rosenblum G, Hofmann H, Löw C. Angew Chem Int Ed Engl 59 19121-19128 (2020)
  20. An Optimized Screen Reduces the Number of GA Transporters and Provides Insights Into Nitrate Transporter 1/Peptide Transporter Family Substrate Determinants. Wulff N, Ernst HA, Jørgensen ME, Lambertz S, Maierhofer T, Belew ZM, Crocoll C, Motawia MS, Geiger D, Jørgensen FS, Mirza O, Nour-Eldin HH. Front Plant Sci 10 1106 (2019)
  21. Functional implications and ubiquitin-dependent degradation of the peptide transporter Ptr2 in Saccharomyces cerevisiae. Kawai K, Moriya A, Uemura S, Abe F. Eukaryot Cell 13 1380-1392 (2014)
  22. 3D-printed holders for in meso in situ fixed-target serial X-ray crystallography. Huang CY, Meier N, Caffrey M, Wang M, Olieric V. J Appl Crystallogr 53 854-859 (2020)
  23. Lipid-like Peptides can Stabilize Integral Membrane Proteins for Biophysical and Structural Studies. Veith K, Martinez Molledo M, Almeida Hernandez Y, Josts I, Nitsche J, Löw C, Tidow H. Chembiochem 18 1735-1742 (2017)
  24. Versatile microporous polymer-based supports for serial macromolecular crystallography. Martiel I, Beale JH, Karpik A, Huang CY, Vera L, Olieric N, Wranik M, Tsai CJ, Mühle J, Aurelius O, John J, Högbom M, Wang M, Marsh M, Padeste C. Acta Crystallogr D Struct Biol 77 1153-1167 (2021)
  25. A simple mathematical approach to the analysis of polypharmacology and polyspecificity data. Maggiora G, Gokhale V. F1000Res 6 Chem Inf Sci-788 (2017)
  26. Critical role of a conserved transmembrane lysine in substrate recognition by the proton-coupled oligopeptide transporter YjdL. Jensen JM, Aduri NG, Prabhala BK, Jahnsen R, Franzyk H, Mirza O. Int J Biochem Cell Biol 55 311-317 (2014)
  27. Letter The helical propensity of the extracellular loop is responsible for the substrate specificity of Fe(III)-phytosiderophore transporters. Harada E, Sugase K, Namba K, Murata Y. FEBS Lett 590 4617-4627 (2016)
  28. Extracellular domain of PepT1 interacts with TM1 to facilitate substrate transport. Shen J, Hu M, Fan X, Ren Z, Portioli C, Yan X, Rong M, Zhou M. Structure 30 1035-1041.e3 (2022)
  29. Cryo-EM Structure of an Atypical Proton-Coupled Peptide Transporter: Di- and Tripeptide Permease C. Killer M, Finocchio G, Mertens HDT, Svergun DI, Pardon E, Steyaert J, Löw C. Front Mol Biosci 9 917725 (2022)
  30. Engineering and functional characterization of a proton-driven β-lactam antibiotic translocation module for bionanotechnological applications. Stauffer M, Ucurum Z, Harder D, Fotiadis D. Sci Rep 11 17205 (2021)
  31. Low-dose in situ prelocation of protein microcrystals by 2D X-ray phase-contrast imaging for serial crystallography. Martiel I, Huang CY, Villanueva-Perez P, Panepucci E, Basu S, Caffrey M, Pedrini B, Bunk O, Stampanoni M, Wang M. IUCrJ 7 1131-1141 (2020)
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