View source for 9pfz


==Architecture of human Voltage Dependent Anion Channel 1 in nanodiscs==
<StructureSection load='9pfz' size='340' side='right'caption='[[9pfz]], [[Resolution|resolution]] 5.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9pfz]] 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=9PFZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9PFZ 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]] 5.4&#8491;</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=9pfz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9pfz OCA], [https://pdbe.org/9pfz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9pfz RCSB], [https://www.ebi.ac.uk/pdbsum/9pfz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9pfz ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/VDAC1_HUMAN VDAC1_HUMAN] Forms a channel through the mitochondrial outer membrane and also the plasma membrane. The channel at the outer mitochondrial membrane allows diffusion of small hydrophilic molecules; in the plasma membrane it is involved in cell volume regulation and apoptosis. It adopts an open conformation at low or zero membrane potential and a closed conformation at potentials above 30-40 mV. The open state has a weak anion selectivity whereas the closed state is cation-selective. May participate in the formation of the permeability transition pore complex (PTPC) responsible for the release of mitochondrial products that triggers apoptosis.<ref>PMID:11845315</ref> <ref>PMID:15033708</ref> <ref>PMID:18755977</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Voltage dependent anion channels (VDACs 1, 2 and 3) in the outer mitochondrial membrane control the flux of anions and oxidizable substrates that sustain mitochondrial metabolism. NADH closes VDAC by binding to a pocket, conserved in all isoforms, located in the inner wall of the channel. Previously, we identified the small molecule SC18 that targets the NADH-binding pocket of VDAC1 employing computational analysis. Here, we explored the interaction between SC18 and VDAC1 using High-resolution Nuclear Magnetic Resonance spectroscopy and Molecular Dynamics simulations. Atomically resolved data precisely confirmed the computational results, showing that SC18 binds to a site on VDAC1 that partially overlaps with the NADH binding pocket. SC18, in the presence of NADH blocked the conductance of VDAC1 reconstituted in lipid bilayers. To determine the metabolic effect of SC18, we combined readouts of mitochondrial metabolism and glycolysis with functional metabolomics and proteomics. Short-term treatment with SC18 inhibited mitochondrial metabolism and ATP production. Treatment over 24 h and 48 h further reduced mitochondrial uptake of pyruvate and glutamine, utilization of tricarboxylic acid cycle intermediates, as well as lipid, DNA and amino acid synthesis. Concomitant with the inhibition of mitochondrial metabolism, cellular uptake of glucose and glutamine increased in parallel with augmented lactate release. These results indicate that compensatory enhanced glycolysis sustains ATP production after impaired mitochondrial function induced by SC18 blockage of VDAC1. Our work set a mechanistic foundation for VDAC1 inhibition as a novel strategy to target and reprogram cancer metabolism through modulation of the biosynthetic ability of mitochondria.

Small Molecule Inhibition of VDAC1 Reroutes Mitochondrial Metabolite Flux.,Modaresi SM, Zhang L, Saei AA, Degen M, Khavani M, Gharibi H, Vegvari A, Ye Z, Zhang J, Pavlov E, Jonas EA, Tew KD, Hiller S, Townsend DM, Maldonado EN Mol Cells. 2026 May 13:100369. doi: 10.1016/j.mocell.2026.100369. PMID:42134653<ref>PMID:42134653</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9pfz" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Degen M]]
[[Category: Hiller S]]
[[Category: Modaresi SM]]