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=='''2JLN'''== | =='''2JLN'''== | ||
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''> | <StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''> | ||
2JLN is one of the conformations of Mhp1, which is a membrane secondary transporter. | |||
The main information of this Proteopedia page come from the article : Structure and Molecular Mechanism of a Nucleobase-Cation-Symport-1 Family Transporter.<ref>PMID 18927357</ref> | |||
== '''Function''' == | == '''Function''' == | ||
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Mhp1 is a trans-membrane protein bellowing to the nucleobase-cation-symport-1 (NCS1) transporter family from Microbacterium liquefaciens. | Mhp1 is a trans-membrane protein bellowing to the nucleobase-cation-symport-1 (NCS1) transporter family from Microbacterium liquefaciens. | ||
A secondary transporter, like Mhp1, effects the cellular uptake and release of a wide range of substances across biological membranes in all organisms. This is done by coupling the uphill movement of the substrate against its concentration gradient with the energetically favorable downhill gradient of a second substrate, often a proton or a cation. The kinetics and thermodynamics of the transporters can be explained by their alternating conformations. | A secondary transporter, like Mhp1, effects the cellular uptake and release of a wide range of substances across biological membranes in all organisms. This is done by coupling the uphill movement of the substrate against its concentration gradient with the energetically favorable downhill gradient of a second substrate, often a proton or a cation. The kinetics and thermodynamics of the transporters can be explained by their alternating conformations.<ref name="art2">PMID 20413494</ref> | ||
In the case of Mhp1, it allows the sodium dependent income of indolyl methyl- and benzyl-hydantoins (''Figure 1'') in the cell. Those are part of a salvage metabolic pathway leading to their conversion in amino acids. | In the case of Mhp1, it allows the sodium dependent income of indolyl methyl- and benzyl-hydantoins (''Figure 1'') in the cell. Those are part of a salvage metabolic pathway leading to their conversion in amino acids. | ||
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Transporters from the NCS1 family are also important in the toxicity of the antifungal agent, 5‐flucytosine and mutations in the proteins can lead to drug resistance. Mhp1 is an excellent model system for elucidating how substrates or inhibitors, including drugs, are recognised at the molecular level and then taken up into cells by members of the NCS1 transporter family. | Transporters from the NCS1 family are also important in the toxicity of the antifungal agent, 5‐flucytosine and mutations in the proteins can lead to drug resistance. Mhp1 is an excellent model system for elucidating how substrates or inhibitors, including drugs, are recognised at the molecular level and then taken up into cells by members of the NCS1 transporter family. | ||
Mhp1 is of more general significance because it is also structurally homologous to other proteins in different subfamilies of the superfamily of secondary transporters. The study of the mechanisms of Mhp1 enables the understanding of other members of this family too. Members of the neurotransmitter‐sodium‐symport family (NSS), solute‐sodium‐symporter family (SSS) and amino acid‐polyamine‐organocation family (APC) are secondary transporters similar to Mhp1. They play important roles in human physiology, being responsible for the accumulation of molecules such as neurotransmitters, sugars, amino acids and drugs into cells. | Mhp1 is of more general significance because it is also structurally homologous to other proteins in different subfamilies of the superfamily of secondary transporters. The study of the mechanisms of Mhp1 enables the understanding of other members of this family too. Members of the neurotransmitter‐sodium‐symport family (NSS), solute‐sodium‐symporter family (SSS) and amino acid‐polyamine‐organocation family (APC) are secondary transporters similar to Mhp1. They play important roles in human physiology, being responsible for the accumulation of molecules such as neurotransmitters, sugars, amino acids and drugs into cells.<ref>PMID 24952894</ref> | ||
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=='''Disease'''== | =='''Disease'''== | ||
Dysfunction of members of the transporters family in humans can lead to diseases including neurological and kidney disorders. Other members are implicated in cancer as they can supply tumor cells with nutrients, cause drug resistance and/or provide a means of treatment. | Dysfunction of members of the transporters family in humans can lead to diseases including neurological and kidney disorders. Other members are implicated in cancer as they can supply tumor cells with nutrients, cause drug resistance and/or provide a means of treatment.<ref name="art2" /> | ||
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The central bundle is composed of TMs 1 and 2, twined to the TMs 6 and 7 respectively. In addition, the protein presents a V-shape structure formed by TMs 3 to 5, twined to TMs 8 to 10 (''Figure 2''). | The central bundle is composed of TMs 1 and 2, twined to the TMs 6 and 7 respectively. In addition, the protein presents a V-shape structure formed by TMs 3 to 5, twined to TMs 8 to 10 (''Figure 2''). | ||
TM5 and TM10 are 'flexible helices' because they bend during the state transitions. | TM5 and TM10 are 'flexible helices' because they bend during the state transitions.<ref name="art2" /> | ||
The substrate- and cation-binding sites are located in the space between the central four-helix-bundle and the outer helix layer. | The substrate- and cation-binding sites are located in the space between the central four-helix-bundle and the outer helix layer. | ||
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Experiments have shown that sodium increases the affinity of benzyl-hydantoin for Mhp1 and reciprocally benzyl-hydantoin increases the affinity of sodium for Mhp1. | Experiments have shown that sodium increases the affinity of benzyl-hydantoin for Mhp1 and reciprocally benzyl-hydantoin increases the affinity of sodium for Mhp1. | ||
Indeed, the presence of benzyl-hydantoin in Mhp1 binding site blocks the pathway of the sodium ion to the extracellular side. | Indeed, the presence of benzyl-hydantoin in Mhp1 binding site blocks the pathway of the sodium ion to the extracellular side.<ref name="art2" /> | ||
Therefore, the binding of the substrate and the cation are closely coupled. | Therefore, the binding of the substrate and the cation are closely coupled. | ||
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The binding of the substrate in the binding site leads to a switch from the outward-facing open state to the outward-facing occluded state. The TM10 arrangement changes (''Figure 4.C'') and closes the access to the “OUT” side space of the membrane (''Figure 5.A''). | The binding of the substrate in the binding site leads to a switch from the outward-facing open state (2JLN) to the outward-facing occluded state ([[4d1b]]). The TM10 arrangement changes (''Figure 4.C'') and closes the access to the “OUT” side space of the membrane (''Figure 5.A''). | ||
Then, there is a change from the outward-facing occluded state to the inward-facing occluded state. (''Figure 5.B'') The substrate-binding site is occluded from the inside of the membrane. It seems that the movement involves the helix bundle of TMs 3 and 8. Moreover, researchers are working on the possibility of a coordinated shifting of TMs 1 and 6 shift with TMs 3 and 8. | Then, there is a change from the outward-facing occluded state to the inward-facing occluded state ([[4d1a]]). (''Figure 5.B'') The substrate-binding site is occluded from the inside of the membrane. It seems that the movement involves the helix bundle of TMs 3 and 8. Moreover, researchers are working on the possibility of a coordinated shifting of TMs 1 and 6 shift with TMs 3 and 8. | ||
Eventually, there is a switch from the inward-facing occluded state to the inward-facing open state. This allows the release of the substrate in the cytoplasm. However, the structures involved in the change still be unclear (''Figure 5.C''). | Eventually, there is a switch from the inward-facing occluded state to the inward-facing open state ([[2x79]]). This allows the release of the substrate in the cytoplasm. However, the structures involved in the change still be unclear (''Figure 5.C''). | ||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||