Drug and peptide transport in humans
From Proteopedia
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| - | <scene name='10/1066775/7pmx/ | + | <scene name='10/1066775/7pmx/3'>PepT1 is a 708-amino acid protein</scene> with an extracellular domain (beta sheets), and a transmembrane transporter domain (alpha helices) with a cytoplasmic amphipathic linker (green protrusion). The latter looks like the '''toe of a boot''' formed by the linker (toe) with the transmembrane domain. The function of the extracellular and cytoplasmic linker domains are not well understood, although the extracellular domain appears to be important in transport<ref name="cytodom">PMID: 35580608</ref>. |
The transmembrane domain has a <scene name='10/1066775/7pmx_phobic_polar/1'>predominantly hydrophobic surface</scene> (enabling it to sit within the lipid bilayer membrane) which is <scene name='10/1066775/7pmx_phobic_polar/2'>devoid of charges</scene>. The cytoplamic linker "toe" has a net positive charge, enabling it to bind to the inner leaflet of the lipid bilayer, which typically has a negative charge. | The transmembrane domain has a <scene name='10/1066775/7pmx_phobic_polar/1'>predominantly hydrophobic surface</scene> (enabling it to sit within the lipid bilayer membrane) which is <scene name='10/1066775/7pmx_phobic_polar/2'>devoid of charges</scene>. The cytoplamic linker "toe" has a net positive charge, enabling it to bind to the inner leaflet of the lipid bilayer, which typically has a negative charge. | ||
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In 2021, Killer ''et al.'' reported human PepT1 structures in outward-open conformations (with and without bound dipeptide)<ref name="kl" />. This greatly furthered understanding of the transport mechanism. In December, 2024, no additional structures with outward-open conformations have been published. | In 2021, Killer ''et al.'' reported human PepT1 structures in outward-open conformations (with and without bound dipeptide)<ref name="kl" />. This greatly furthered understanding of the transport mechanism. In December, 2024, no additional structures with outward-open conformations have been published. | ||
| - | <scene name='10/1066775/Chimerax-morph-pdb/2'>A morph between outward-open and inward-open (partially occluded) conformations</scene> ([[7pmx]] and [[7pmy]]) of the transmembrane domain (extracellular domain hidden) illustrates the rocker-switch-like mechanism of transport. (7pmy is actually human PepT2, a different transporter with a very similar structure, and about 65% sequence identify with PepT1 in the transporter core domain.) This morph is oversimplified. Killer ''et al.'' actually captured 4 different conformations, revealing additional details of the rocker-switch mechanism. Their supplementary materials include a [https://www.science.org/doi/suppl/10.1126/sciadv.abk3259/suppl_file/sciadv.abk3259_movie_s1.zip revealing morph movie] (see also [https://www.science.org/doi/suppl/10.1126/sciadv.abk3259/suppl_file/sciadv.abk3259_sm.pdf the movie explanation]) that includes all 4 conformations. | + | <scene name='10/1066775/Chimerax-morph-pdb/2'>A morph between outward-open and inward-open (partially occluded) conformations</scene> ([[7pmx]] and [[7pmy]]) of the transmembrane domain (extracellular domain hidden) illustrates the rocker-switch-like mechanism of transport. (7pmy is actually human PepT2, a different transporter with a very similar structure, and about 65% sequence identify with PepT1 in the transporter core domain.) This morph is oversimplified. Killer ''et al.'' actually captured 4 different conformations, revealing additional details of the rocker-switch mechanism. Their '''supplementary materials''' include a [https://www.science.org/doi/suppl/10.1126/sciadv.abk3259/suppl_file/sciadv.abk3259_movie_s1.zip revealing morph movie] (see also [https://www.science.org/doi/suppl/10.1126/sciadv.abk3259/suppl_file/sciadv.abk3259_sm.pdf the movie explanation]) that includes '''all 4 conformations'''. |
<scene name='10/1066775/Chimerax-morph-pdb/3'>This view looks down into the outward-facing channel, while it closes and opens</scene>. Rotate to position the opposite side in front to see into the inward-facing open but partially occluded channel. | <scene name='10/1066775/Chimerax-morph-pdb/3'>This view looks down into the outward-facing channel, while it closes and opens</scene>. Rotate to position the opposite side in front to see into the inward-facing open but partially occluded channel. | ||
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| + | <center><font color="red">If morph animations fail to start, click the green link again.</font></center> | ||
==Channel Shapes and Sizes== | ==Channel Shapes and Sizes== | ||
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* The coordinates of the extracellular domain of 7pmx, sequence 381-579, were deleted from the [[PDB file]] using a [[plain text editor]]. | * The coordinates of the extracellular domain of 7pmx, sequence 381-579, were deleted from the [[PDB file]] using a [[plain text editor]]. | ||
* The coordinates of the extracellular domain of 7pmy, sequence 403-606, were deleted from the [[PDB file]]. | * The coordinates of the extracellular domain of 7pmy, sequence 403-606, were deleted from the [[PDB file]]. | ||
| + | These PDB files were used for making the morph, and for [[PACUPP]]. | ||
===Morph=== | ===Morph=== | ||
| - | [[Morphs]] were generated | + | [[Morphs]] were generated with [https://fatcat.godziklab.org/ FATCAT], with the [https://proteopedia.org/cgi-bin/morph Proteopedia PyMOL Morpher], and with [[ChimeraX]]. The dipeptide ligand was absent in the FATCAT and Proteopedia/PyMOL morphs, but was retained in the ChimeraX morph PDB file. A ChimeraX morph between the isolated transmembrane domains, with hydrogen atoms deleted, was used for the above scenes, [[Image:7pmx-y-morph-chimerax-xmemb-noh.pdb.gz]]. |
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| + | Some steps in making the morph in ChimeraX are easily done from the menus, e.g. Tools, Structure Analysis, MatchMaker for superposition. Other steps must be done from commands. The complete command file for making a morph between the full-length PDB files is [https://proteopedia.org/wiki/images/a/a8/7pmx-y-morph.cxc 7pmx-y-morph.cxc]. The transmembrane domain PDB files were simply dragged and dropped into ChimeraX, instead of loading from the [[wwPDB]]. | ||
</StructureSection> | </StructureSection> | ||
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| + | ==See Also== | ||
| + | *[https://pdb101.rcsb.org/learn/flyers-posters-and-calendars/calendar/2025-calendar-the-structural-biology-of-nutrition Structural Biology of Nutrition] at PDB-101 highlights the structures featured here (look for the brown background). | ||
==References and Notes== | ==References and Notes== | ||
<references /> | <references /> | ||
Current revision
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See Also
- Structural Biology of Nutrition at PDB-101 highlights the structures featured here (look for the brown background).
References and Notes
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Killer M, Wald J, Pieprzyk J, Marlovits TC, Low C. Structural snapshots of human PepT1 and PepT2 reveal mechanistic insights into substrate and drug transport across epithelial membranes. Sci Adv. 2021 Nov 5;7(45):eabk3259. doi: 10.1126/sciadv.abk3259. Epub 2021 Nov 3. PMID:34730990 doi:http://dx.doi.org/10.1126/sciadv.abk3259
- ↑ Shen J, Hu M, Fan X, Ren Z, Portioli C, Yan X, Rong M, Zhou M. Extracellular domain of PepT1 interacts with TM1 to facilitate substrate transport. Structure. 2022 Jul 7;30(7):1035-1041.e3. PMID:35580608 doi:10.1016/j.str.2022.04.011
- ↑ 2.0 Å pseudoatoms are called "extra fine detail" in PACUPP. It defaults to "fine" (3.0 Å), and also offers "very fine" (2.4 Å) or user-specified diameters.
