9wbr: Difference between revisions

Latest revision as of 04:58, 24 June 2026

The structure of glycine transport 2 in apo state

Structural highlights

9wbr is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.13Å
Ligands:	CL
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SC6A5_HUMAN Hereditary hyperekplexia. The disease is caused by variants affecting the gene represented in this entry.

Function

SC6A5_HUMAN Sodium- and chloride-dependent glycine transporter (PubMed:10381548, PubMed:10606742, PubMed:16751771, PubMed:31370103, PubMed:9845349). Terminates the action of glycine by its high affinity sodium-dependent reuptake into presynaptic terminals (PubMed:9845349). May be responsible for the termination of neurotransmission at strychnine-sensitive glycinergic synapses (PubMed:9845349).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] Lacks sodium- and chloride-dependent glycine transporter activity.^[7] Lacks sodium- and chloride-dependent glycine transporter activity.^[8]

Publication Abstract from PubMed

Neuronal human glycine transporter 2 (hGlyT2) plays a critical role in maintaining glycinergic neurotransmission via the reuptake of glycine into presynaptic neurons by using the driving force of sodium and chloride ion gradients. hGlyT2 represents an important drug target for analgesic purpose. However, its structure and the molecular mechanisms remain elusive. Here, we report structures of hGlyT2 in three functional states, including the apo state, the substrate glycine-bound state, and the inhibitor-bound states. The apo state of hGlyT2 adopts an inward conformation. The substrate glycine binds at the central pocket of hGlyT2 in its occluded conformation. Both inhibitors, ORG25543 and opiranserin, bind to an allosteric site, which is vertical to the extracellular tunnel, buried under the extracellular loop 4 (EL4) and near to the transmembrane helix 1b (TM1b). These inhibitors act as wedges to prevent the inward movement of TM1b and closure of the extracellular gate. Further structural analysis reveals both global and local conformational changes associated with the ions and glycine binding and release. These structures define the mechanisms governing transport and allosteric inhibition in hGlyT2, providing a blueprint for further development of non-opioid analgesics targeting hGlyT2.

Transport and inhibition mechanisms of human glycine transporter 2.,Ji W, Yu Y, Liu Z, Su J, Wang Q, Lai M, Wu JX Nat Commun. 2026 Apr 16;17(1):5321. doi: 10.1038/s41467-026-71935-6. PMID:41991951^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Gallagher MJ, Burgess LH, Brunden KR. Characterization of multiple forms of the human glycine transporter type-2. Brain Res Mol Brain Res. 1999 Jun 18;70(1):101-15. doi: , 10.1016/s0169-328x(99)00135-7. PMID:10381548 doi:https://dx.doi.org/10.1016/s0169-328x(99)00135-7
↑ Evans J, Herdon H, Cairns W, O'Brien E, Chapman C, Terrett J, Gloger I. Cloning, functional characterisation and population analysis of a variant form of the human glycine type 2 transporter. FEBS Lett. 1999 Dec 17;463(3):301-6. doi: 10.1016/s0014-5793(99)01636-1. PMID:10606742 doi:https://dx.doi.org/10.1016/s0014-5793(99)01636-1
↑ Rees MI, Harvey K, Pearce BR, Chung SK, Duguid IC, Thomas P, Beatty S, Graham GE, Armstrong L, Shiang R, Abbott KJ, Zuberi SM, Stephenson JB, Owen MJ, Tijssen MA, van den Maagdenberg AM, Smart TG, Supplisson S, Harvey RJ. Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nat Genet. 2006 Jul;38(7):801-6. doi: 10.1038/ng1814. Epub 2006 Jun 4. PMID:16751771 doi:https://dx.doi.org/10.1038/ng1814
↑ Kitzenmaier A, Schaefer N, Kasaragod VB, Polster T, Hantschmann R, Schindelin H, Villmann C. The P429L loss of function mutation of the human glycine transporter 2 associated with hyperekplexia. Eur J Neurosci. 2019 Dec;50(12):3906-3920. doi: 10.1111/ejn.14533. Epub 2019 Sep , 5. PMID:31370103 doi:https://dx.doi.org/10.1111/ejn.14533
↑ Sarmiento-Jimenez J, Felipe R, Nunez E, Ferrando-Munoz A, Benito-Munoz C, Gago F, Vazquez J, Camafeita E, Clement E, Wilson B, Lopez-Corcuera B. A New GlyT2 Variant Associated with Hyperekplexia. Int J Mol Sci. 2025 Jul 14;26(14):6753. doi: 10.3390/ijms26146753. PMID:40725001 doi:https://dx.doi.org/10.3390/ijms26146753
↑ Morrow JA, Collie IT, Dunbar DR, Walker GB, Shahid M, Hill DR. Molecular cloning and functional expression of the human glycine transporter GlyT2 and chromosomal localisation of the gene in the human genome. FEBS Lett. 1998 Nov 20;439(3):334-40. doi: 10.1016/s0014-5793(98)01390-8. PMID:9845349 doi:https://dx.doi.org/10.1016/s0014-5793(98)01390-8
↑ Gallagher MJ, Burgess LH, Brunden KR. Characterization of multiple forms of the human glycine transporter type-2. Brain Res Mol Brain Res. 1999 Jun 18;70(1):101-15. doi: , 10.1016/s0169-328x(99)00135-7. PMID:10381548 doi:https://dx.doi.org/10.1016/s0169-328x(99)00135-7
↑ Gallagher MJ, Burgess LH, Brunden KR. Characterization of multiple forms of the human glycine transporter type-2. Brain Res Mol Brain Res. 1999 Jun 18;70(1):101-15. doi: , 10.1016/s0169-328x(99)00135-7. PMID:10381548 doi:https://dx.doi.org/10.1016/s0169-328x(99)00135-7
↑ Ji W, Yu Y, Liu Z, Su J, Wang Q, Lai M, Wu JX. Transport and inhibition mechanisms of human glycine transporter 2. Nat Commun. 2026 Apr 16;17(1):5321. doi: 10.1038/s41467-026-71935-6. PMID:41991951 doi:https://dx.doi.org/10.1038/s41467-026-71935-6

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Gallagher MJ, Burgess LH, Brunden KR. Characterization of multiple forms of the human glycine transporter type-2. Brain Res Mol Brain Res. 1999 Jun 18;70(1):101-15. doi: , 10.1016/s0169-328x(99)00135-7. PMID:10381548 doi:https://dx.doi.org/10.1016/s0169-328x(99)00135-7

[2] Evans J, Herdon H, Cairns W, O'Brien E, Chapman C, Terrett J, Gloger I. Cloning, functional characterisation and population analysis of a variant form of the human glycine type 2 transporter. FEBS Lett. 1999 Dec 17;463(3):301-6. doi: 10.1016/s0014-5793(99)01636-1. PMID:10606742 doi:https://dx.doi.org/10.1016/s0014-5793(99)01636-1

[3] Rees MI, Harvey K, Pearce BR, Chung SK, Duguid IC, Thomas P, Beatty S, Graham GE, Armstrong L, Shiang R, Abbott KJ, Zuberi SM, Stephenson JB, Owen MJ, Tijssen MA, van den Maagdenberg AM, Smart TG, Supplisson S, Harvey RJ. Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nat Genet. 2006 Jul;38(7):801-6. doi: 10.1038/ng1814. Epub 2006 Jun 4. PMID:16751771 doi:https://dx.doi.org/10.1038/ng1814

[4] Kitzenmaier A, Schaefer N, Kasaragod VB, Polster T, Hantschmann R, Schindelin H, Villmann C. The P429L loss of function mutation of the human glycine transporter 2 associated with hyperekplexia. Eur J Neurosci. 2019 Dec;50(12):3906-3920. doi: 10.1111/ejn.14533. Epub 2019 Sep , 5. PMID:31370103 doi:https://dx.doi.org/10.1111/ejn.14533

[5] Sarmiento-Jimenez J, Felipe R, Nunez E, Ferrando-Munoz A, Benito-Munoz C, Gago F, Vazquez J, Camafeita E, Clement E, Wilson B, Lopez-Corcuera B. A New GlyT2 Variant Associated with Hyperekplexia. Int J Mol Sci. 2025 Jul 14;26(14):6753. doi: 10.3390/ijms26146753. PMID:40725001 doi:https://dx.doi.org/10.3390/ijms26146753

[6] Morrow JA, Collie IT, Dunbar DR, Walker GB, Shahid M, Hill DR. Molecular cloning and functional expression of the human glycine transporter GlyT2 and chromosomal localisation of the gene in the human genome. FEBS Lett. 1998 Nov 20;439(3):334-40. doi: 10.1016/s0014-5793(98)01390-8. PMID:9845349 doi:https://dx.doi.org/10.1016/s0014-5793(98)01390-8

[7] Gallagher MJ, Burgess LH, Brunden KR. Characterization of multiple forms of the human glycine transporter type-2. Brain Res Mol Brain Res. 1999 Jun 18;70(1):101-15. doi: , 10.1016/s0169-328x(99)00135-7. PMID:10381548 doi:https://dx.doi.org/10.1016/s0169-328x(99)00135-7

[8] Gallagher MJ, Burgess LH, Brunden KR. Characterization of multiple forms of the human glycine transporter type-2. Brain Res Mol Brain Res. 1999 Jun 18;70(1):101-15. doi: , 10.1016/s0169-328x(99)00135-7. PMID:10381548 doi:https://dx.doi.org/10.1016/s0169-328x(99)00135-7

[9] Ji W, Yu Y, Liu Z, Su J, Wang Q, Lai M, Wu JX. Transport and inhibition mechanisms of human glycine transporter 2. Nat Commun. 2026 Apr 16;17(1):5321. doi: 10.1038/s41467-026-71935-6. PMID:41991951 doi:https://dx.doi.org/10.1038/s41467-026-71935-6

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[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9wbr is ON HOLD
+==The structure of glycine transport 2 in apo state==
+<StructureSection load='9wbr' size='340' side='right'caption='[[9wbr]], [[Resolution|resolution]] 3.13&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9wbr]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9WBR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9WBR FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.13&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9wbr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9wbr OCA], [https://pdbe.org/9wbr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9wbr RCSB], [https://www.ebi.ac.uk/pdbsum/9wbr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9wbr ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/SC6A5_HUMAN SC6A5_HUMAN] Hereditary hyperekplexia. The disease is caused by variants affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/SC6A5_HUMAN SC6A5_HUMAN] Sodium- and chloride-dependent glycine transporter (PubMed:10381548, PubMed:10606742, PubMed:16751771, PubMed:31370103, PubMed:9845349). Terminates the action of glycine by its high affinity sodium-dependent reuptake into presynaptic terminals (PubMed:9845349). May be responsible for the termination of neurotransmission at strychnine-sensitive glycinergic synapses (PubMed:9845349).<ref>PMID:10381548</ref> <ref>PMID:10606742</ref> <ref>PMID:16751771</ref> <ref>PMID:31370103</ref> <ref>PMID:40725001</ref> <ref>PMID:9845349</ref>   Lacks sodium- and chloride-dependent glycine transporter activity.<ref>PMID:10381548</ref>   Lacks sodium- and chloride-dependent glycine transporter activity.<ref>PMID:10381548</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Neuronal human glycine transporter 2 (hGlyT2) plays a critical role in maintaining glycinergic neurotransmission via the reuptake of glycine into presynaptic neurons by using the driving force of sodium and chloride ion gradients. hGlyT2 represents an important drug target for analgesic purpose. However, its structure and the molecular mechanisms remain elusive. Here, we report structures of hGlyT2 in three functional states, including the apo state, the substrate glycine-bound state, and the inhibitor-bound states. The apo state of hGlyT2 adopts an inward conformation. The substrate glycine binds at the central pocket of hGlyT2 in its occluded conformation. Both inhibitors, ORG25543 and opiranserin, bind to an allosteric site, which is vertical to the extracellular tunnel, buried under the extracellular loop 4 (EL4) and near to the transmembrane helix 1b (TM1b). These inhibitors act as wedges to prevent the inward movement of TM1b and closure of the extracellular gate. Further structural analysis reveals both global and local conformational changes associated with the ions and glycine binding and release. These structures define the mechanisms governing transport and allosteric inhibition in hGlyT2, providing a blueprint for further development of non-opioid analgesics targeting hGlyT2.
-Authors:
+Transport and inhibition mechanisms of human glycine transporter 2.,Ji W, Yu Y, Liu Z, Su J, Wang Q, Lai M, Wu JX Nat Commun. 2026 Apr 16;17(1):5321. doi: 10.1038/s41467-026-71935-6. PMID:41991951<ref>PMID:41991951</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 9wbr" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Wu JX]]
+[[Category: JI WM]]

9wbr: Difference between revisions

Latest revision as of 04:58, 24 June 2026

The structure of glycine transport 2 in apo state

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

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