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(Created full sandbox page for 8VAC: added structure overview, functional analysis, ligand-binding highlights, reference citation, image gallery, and uploaded figure.)
 
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= Cryo-EM Structure of Human Serum Albumin (2024) =
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''By JHANVI KATH BI3323-Aug 2025''
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<table width="90%" border="0"><tr><td>
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== Reference Study ==
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{| align="left"
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Catalano C., Lucier K. W., To D., Senko S., Tran N. L., Farwell A. C., Silva S. M., Dip P. V., Poweleit N., Scapin G. (2024).
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|-
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''The CryoEM structure of human serum albumin in complex with ligands.''
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|
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Journal of Structural Biology, 216(3):108105.
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|}
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DOI: 10.1016/j.jsb.2024.108105
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</td></tr><tr><td>
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<span style="font-size:180%"><b> Cryo-EM structures of the E. coli Ton and Tol
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PDB ID: 8VAC
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motor complexes</b></span>
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</td></tr><tr><td>
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<span style="font-size:110%">
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== Structure ==
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Paul C. Rosen, Samantha M. Horwitz, Daniel J. Brooks, Erica Kim, Joseph A. Ambarian, Lidia Waidmann, Katherine M. Davis and Gary Yellen
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<StructureSection load='8VAC' size='340' side='right' caption='Cryo-EM structure of human serum albumin bound to ligands (8VAC, 2024)' scene=''>
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Herve Celia, Bridgette M. Beach, Istvan Botos ,Rodolfo Ghirlando, Denis Duché ,RolandLloubes2 & Susan K. Buchanan
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Human Serum Albumin (HSA) is the dominant plasma protein responsible for transport, buffering, and molecular trafficking.
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Nature Communications volume 16, Article number: 5506 (2025) [ https://doi.org/10.1038/s41467-025-61286-z] 
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The 2024 cryo-EM map (8VAC) captures HSA in complex with multiple ligands under near-physiological biochemical conditions, revealing:
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</span>
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</td></tr></table>
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==Structure Tour==
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* Three-domain organization (I, II, III), each with A/B subdomains.
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* A flexible, heart-shaped tertiary fold.
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* Multiple hydrophobic binding pockets for drugs, fatty acids, and endogenous molecules.
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* Conformational adjustments in Sudlow sites I and II upon ligand engagement.
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* Domain movements consistent with adaptive ligand accommodation.
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<StructureSection load='4omz' size='350' side='right' caption='Cryo-EM structures of the E. coli Ton and Tol motor complexes (PDB entry [[9DDM]])' scene=''>
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The loaded 8VAC structure provides a solution-like, high-fidelity representation of the molecule.
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===Abstract===
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</StructureSection>
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The Ton and Tol systems are proton‑driven motor complexes that are essential for high‑affinity nutrient uptake and for maintaining outer‑membrane integrity in Gram‑negative bacteria. Their activity depends on coordinated interactions among the inner‑membrane proteins ExbB–ExbD–TonB and TolQ–TolR–TolA, but the structural basis of these interactions has been poorly understood. This paper presents near-atomic-resolution cryo-EM structures of both complexes, revealing a conserved architecture in which a pentameric ExbB or TolQ ring encloses a dimeric ExbD or TolR transmembrane segment.
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===Overview ===
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== Function ==
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Gram-negative bacteria use specialized molecular “motors” in their inner membrane to move energy from the proton motive force (pmf) to the cell surface. The E. coli TolAQR and TonB–ExbBD complexes are two such molecular motors in teh inner membrane that harness the proton motive force (pmf) to drive critical cell envelope processes. Despite acting in parallel pathways with the Tol system maintaining outer membrane integrity and the Ton system powering nutrient import, both complexes share similar architectural design: : pentameric scaffold, embedded proton-linked residues, and a single force-transducing helix (TolA or TonB) that connects the pmf machinery to the cell surface. High-resolution cryo-EM structures shown in this paper reveal how these assemblies are organized and how their subunits couple pmf to mechanical action.
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HSA acts as a systemic transport hub in the bloodstream.
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Major physiological roles include:
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* Binding and transport of fatty acids, bilirubin, hormones, and xenobiotics.
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* Strong influence on pharmacokinetics for albumin-bound drugs.
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* Maintenance of colloid osmotic pressure.
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* Participation in pH buffering and redox balance.
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The 8VAC cryo-EM structure highlights how the protein repositions domains to optimize ligand engagement.
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===Structure of the E. coli TolAQR Complex===
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== Disease ==
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The cryo-EM structure of the TolA–TolQ–TolR complex was obtained after removing the flexible periplasmic portion of TolA which created heterogeneity. This removal was done via a TEV-cleavable construct. The resulting assembly has a 5:2:2 TolQ:TolR:TolA stoichiometry. TolQ forms a pentameric scaffold of seven α-helices per subunit, including three tilted transmembrane helices shaped by conserved proline-induced kinks. TolR forms a dimer within the central hydrophobic pore, with its essential residue Asp23 positioned near a ring of TolQ Thr138/Thr178, creating a proton-linked polar gate. Two TolA transmembrane helices bind peripherally through the conserved SHLS motif, with His22 making key contacts with TolQ. The cytoplasmic domain of TolQ helices are intrinsically flexible showing dynamic nature during pmf driven activities
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Structural or concentration changes in HSA correlate with many pathologies:
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* Hypoalbuminemia in liver disease, sepsis, nephrotic syndrome.
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* Glycation and oxidation in diabetes or chronic kidney disease, altering ligand affinity.
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* Hereditary albumin variants, impacting stability and drug-binding profiles.
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* Altered levels in inflammation, cancer, and severe infection influence drug dosing outcomes.
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===Structure of the E. coli TonB–ExbBD Complex===
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Structural mapping enables correlation of clinical conditions with ligand-pocket geometry.
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The E. coli TonB–ExbBD complex is a 1:5:2 assembly in which five ExbB subunits form a tilted-helix pentameric scaffold that encloses a parallel but axially offset dimer of ExbD transmembrane helices. The ExbB pentamer generates a hydrophobic central pore into which the ExbD TM dimer inserts, while the N-terminal cytoplasmic domains of ExbD form an asymmetric pair stabilized by conserved ExbB residues. The TonB forms a single transmembrane helix with a conserved SHLS motif. The transmembrane helix is tilted ~15° in the membrane and interacts with the ExbB through conserved TonB Ser16 and His20. The complex also contains tightly bound phosphatidylethanolamine lipids at ExbB subunit interfaces.
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===References===
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== Relevance ==
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The 8VAC structure is directly applicable to:
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* Drug design – understanding pocket architecture assists affinity and specificity tuning.
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* PK/PD modeling – high-affinity albumin binders require dosage fine-tuning.
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* Albumin-based drug delivery systems – nanoparticles and small molecules utilize albumin’s long circulation time.
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* Biomarker interpretation – albumin concentration is essential in diagnoses and scoring systems.
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Celia, H., Botos, I., Ghirlando, R., Duché, D., Beach, B. M., Lloubes, R., & Buchanan, S. K. (2025). Cryo-EM structures of the E. coli Ton and Tol motor complexes. Nature Communications, 16, 5506. [https://doi.org/10.1038/s41467-025-61286-z](https://doi.org/10.1038/s41467-025-61286-z)
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This structure bridges clinical context and molecular understanding in a single cryo-EM model.
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== Structural Highlights ==
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Below are placeholder SAT scenes that you can replace with your own:
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===About this Page===
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* Overall 3-domain organization:
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<!-- This section ensures you get credit -->
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<scene name="/sandbox/jhanvi/HSA_8VAC/overall/1">Domain overview</scene>
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This page was created by '''[[User:Your_Username| Niranjana Vinod]]'''.<br>
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University/Institution Name (Indian Institute of Science Education and Research,Pune)
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* Sudlow Site I (Domain IIA):
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<scene name="/sandbox/jhanvi/HSA_8VAC/siteI/1">Primary drug-binding pocket</scene>
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</StructureSection>
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* Sudlow Site II (Domain IIIA):
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<scene name="/sandbox/jhanvi/HSA_8VAC/siteII/1">Secondary drug-binding pocket</scene>
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* Flexibility + domain movements:
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<scene name="/sandbox/jhanvi/HSA_8VAC/flexibility/1">Hinge flexibility</scene>
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== Uploaded Figures ==
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Insert your PNGs here after uploading (instructions below):
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<gallery>
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File:HSA_Overall_Structure.png|Overall Cryo-EM structure of Human Serum Albumin (8VAC)
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File:HSA_Salicylic.png|HSA with salicylic ligand bound
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</gallery>
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== References ==
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<references/>

Current revision

Contents

Cryo-EM Structure of Human Serum Albumin (2024)

By JHANVI KATH BI3323-Aug 2025

Reference Study

Catalano C., Lucier K. W., To D., Senko S., Tran N. L., Farwell A. C., Silva S. M., Dip P. V., Poweleit N., Scapin G. (2024). The CryoEM structure of human serum albumin in complex with ligands. Journal of Structural Biology, 216(3):108105. DOI: 10.1016/j.jsb.2024.108105

PDB ID: 8VAC

Structure

Cryo-EM structure of human serum albumin bound to ligands (8VAC, 2024)

Drag the structure with the mouse to rotate

Function

HSA acts as a systemic transport hub in the bloodstream. Major physiological roles include:

  • Binding and transport of fatty acids, bilirubin, hormones, and xenobiotics.
  • Strong influence on pharmacokinetics for albumin-bound drugs.
  • Maintenance of colloid osmotic pressure.
  • Participation in pH buffering and redox balance.

The 8VAC cryo-EM structure highlights how the protein repositions domains to optimize ligand engagement.

Disease

Structural or concentration changes in HSA correlate with many pathologies:

  • Hypoalbuminemia in liver disease, sepsis, nephrotic syndrome.
  • Glycation and oxidation in diabetes or chronic kidney disease, altering ligand affinity.
  • Hereditary albumin variants, impacting stability and drug-binding profiles.
  • Altered levels in inflammation, cancer, and severe infection influence drug dosing outcomes.

Structural mapping enables correlation of clinical conditions with ligand-pocket geometry.

Relevance

The 8VAC structure is directly applicable to:

  • Drug design – understanding pocket architecture assists affinity and specificity tuning.
  • PK/PD modeling – high-affinity albumin binders require dosage fine-tuning.
  • Albumin-based drug delivery systems – nanoparticles and small molecules utilize albumin’s long circulation time.
  • Biomarker interpretation – albumin concentration is essential in diagnoses and scoring systems.

This structure bridges clinical context and molecular understanding in a single cryo-EM model.

Structural Highlights

Below are placeholder SAT scenes that you can replace with your own:

  • Overall 3-domain organization:
  • Sudlow Site I (Domain IIA):
  • Sudlow Site II (Domain IIIA):
  • Flexibility + domain movements:

Uploaded Figures

Insert your PNGs here after uploading (instructions below):

File:HSA Overall Structure.png

Overall Cryo-EM structure of Human Serum Albumin (8VAC)

File:HSA Salicylic.png

HSA with salicylic ligand bound

References

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