8g8w

From Proteopedia

(Difference between revisions)

Current revision

Molecular mechanism of nucleotide inhibition of human uncoupling protein 1

Structural highlights

8g8w is a 3 chain structure with sequence from Escherichia coli K-12, Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.8Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

UCP1_HUMAN Mitochondrial protein responsible for thermogenic respiration, a specialized capacity of brown adipose tissue and beige fat that participates in non-shivering adaptive thermogenesis to temperature and diet variations and more generally to the regulation of energy balance (By similarity). Functions as a long-chain fatty acid/LCFA and proton symporter, simultaneously transporting one LCFA and one proton through the inner mitochondrial membrane (PubMed:24196960, PubMed:28781081). However, LCFAs remaining associated with the transporter via their hydrophobic tails, it results in an apparent transport of protons activated by LCFAs. Thereby, dissipates the mitochondrial proton gradient and converts the energy of substrate oxydation into heat instead of ATP. Regulates the production of reactive oxygen species/ROS by mitochondria (By similarity).[UniProtKB:P12242]^[1] ^[2]

Publication Abstract from PubMed

Mitochondrial uncoupling protein 1 (UCP1) gives brown adipose tissue of mammals its specialized ability to burn calories as heat for thermoregulation. When activated by fatty acids, UCP1 catalyzes the leak of protons across the mitochondrial inner membrane, short-circuiting the mitochondrion to generate heat, bypassing ATP synthesis. In contrast, purine nucleotides bind and inhibit UCP1, regulating proton leak by a molecular mechanism that is unclear. We present the cryo-electron microscopy structure of the GTP-inhibited state of UCP1, which is consistent with its nonconducting state. The purine nucleotide cross-links the transmembrane helices of UCP1 with an extensive interaction network. Our results provide a structural basis for understanding the specificity and pH dependency of the regulatory mechanism. UCP1 has retained all of the key functional and structural features required for a mitochondrial carrier-like transport mechanism. The analysis shows that inhibitor binding prevents the conformational changes that UCP1 uses to facilitate proton leak.

Structural basis of purine nucleotide inhibition of human uncoupling protein 1.,Jones SA, Gogoi P, Ruprecht JJ, King MS, Lee Y, Zogg T, Pardon E, Chand D, Steimle S, Copeman DM, Cotrim CA, Steyaert J, Crichton PG, Moiseenkova-Bell V, Kunji ERS Sci Adv. 2023 Jun 2;9(22):eadh4251. doi: 10.1126/sciadv.adh4251. Epub 2023 May , 31. PMID:37256948^[3]

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

References

↑ Hoang T, Smith MD, Jelokhani-Niaraki M. Expression, folding, and proton transport activity of human uncoupling protein-1 (UCP1) in lipid membranes: evidence for associated functional forms. J Biol Chem. 2013 Dec 20;288(51):36244-58. PMID:24196960 doi:10.1074/jbc.M113.509935
↑ Zhao L, Wang S, Zhu Q, Wu B, Liu Z, OuYang B, Chou JJ. Specific Interaction of the Human Mitochondrial Uncoupling Protein 1 with Free Long-Chain Fatty Acid. Structure. 2017 Sep 5;25(9):1371-1379.e3. PMID:28781081 doi:10.1016/j.str.2017.07.005
↑ Jones SA, Gogoi P, Ruprecht JJ, King MS, Lee Y, Zögg T, Pardon E, Chand D, Steimle S, Copeman DM, Cotrim CA, Steyaert J, Crichton PG, Moiseenkova-Bell V, Kunji ERS. Structural basis of purine nucleotide inhibition of human uncoupling protein 1. Sci Adv. 2023 Jun 2;9(22):eadh4251. PMID:37256948 doi:10.1126/sciadv.adh4251

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8g8w"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[8g8w]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8G8W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8G8W FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CDL:CARDIOLIPIN'>CDL</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.8&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CDL:CARDIOLIPIN'>CDL</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</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=8g8w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8g8w OCA], [https://pdbe.org/8g8w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8g8w RCSB], [https://www.ebi.ac.uk/pdbsum/8g8w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8g8w ProSAT]</span></td></tr>
 </table>
 == Function ==
-[https://www.uniprot.org/uniprot/UCP1_HUMAN UCP1_HUMAN] Mitochondrial protein responsible for thermogenic respiration, a specialized capacity of brown adipose tissue and beige fat that participates in non-shivering adaptive thermogenesis to temperature and diet variations and more generally to the regulation of energy balance (By similarity). Functions as a long-chain fatty acid/LCFA and proton symporter, simultaneously transporting one LCFA and one proton through the inner mitochondrial membrane (PubMed:24196960). However, LCFAs remaining associated with the transporter via their hydrophobic tails, it results in an apparent transport of protons activated by LCFAs. Thereby, dissipates the mitochondrial proton gradient and converts the energy of substrate oxydation into heat instead of ATP. Regulates the production of reactive oxygen species/ROS by mitochondria (By similarity).[UniProtKB:P12242]<ref>PMID:24196960</ref>
+[https://www.uniprot.org/uniprot/UCP1_HUMAN UCP1_HUMAN] Mitochondrial protein responsible for thermogenic respiration, a specialized capacity of brown adipose tissue and beige fat that participates in non-shivering adaptive thermogenesis to temperature and diet variations and more generally to the regulation of energy balance (By similarity). Functions as a long-chain fatty acid/LCFA and proton symporter, simultaneously transporting one LCFA and one proton through the inner mitochondrial membrane (PubMed:24196960, PubMed:28781081). However, LCFAs remaining associated with the transporter via their hydrophobic tails, it results in an apparent transport of protons activated by LCFAs. Thereby, dissipates the mitochondrial proton gradient and converts the energy of substrate oxydation into heat instead of ATP. Regulates the production of reactive oxygen species/ROS by mitochondria (By similarity).[UniProtKB:P12242]<ref>PMID:24196960</ref> <ref>PMID:28781081</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

8g8w

From Proteopedia

Current revision

Molecular mechanism of nucleotide inhibition of human uncoupling protein 1

Structural highlights

Function

Publication Abstract from PubMed

References

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