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(New page: <table width="90%" border="0"><tr><td> {| align="left" |- | |} </td></tr><tr><td> <span style="font-size:180%"><b> Cryo-EM structures of the E. coli Ton and Tol motor complexes</b></sp...)
Current revision (17:07, 30 November 2025) (edit) (undo)
(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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== Reference Study ==
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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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''The CryoEM structure of human serum albumin in complex with ligands.''
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Journal of Structural Biology, 216(3):108105.
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DOI: 10.1016/j.jsb.2024.108105
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<table width="90%" border="0"><tr><td>
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PDB ID: 8VAC
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{| align="left"
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|-
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|}
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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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== Structure ==
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motor complexes</b></span>
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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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</td></tr><tr><td>
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Human Serum Albumin (HSA) is the dominant plasma protein responsible for transport, buffering, and molecular trafficking.
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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 style="font-size:110%">
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* Three-domain organization (I, II, III), each with A/B subdomains.
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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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* A flexible, heart-shaped tertiary fold.
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Herve Celia, Bridgette M. Beach, Istvan Botos ,Rodolfo Ghirlando, Denis Duché ,RolandLloubes2 & Susan K. Buchanan
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* Multiple hydrophobic binding pockets for drugs, fatty acids, and endogenous molecules.
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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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* Conformational adjustments in Sudlow sites I and II upon ligand engagement.
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</span>
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* Domain movements consistent with adaptive ligand accommodation.
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</td></tr></table>
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==Structure Tour==
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The loaded 8VAC structure provides a solution-like, high-fidelity representation of the molecule.
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</StructureSection>
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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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== Function ==
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===Abstract===
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HSA acts as a systemic transport hub in the bloodstream.
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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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Major physiological roles include:
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===Overall Structure of ===
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* Binding and transport of fatty acids, bilirubin, hormones, and xenobiotics.
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NolR is a member of the '''ArsR/SmtB family''' of transcription factors. The crystal structure reveals that the protein functions as a homodimer. Each monomer folds into a winged helix-turn-helix motif.
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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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Click on "<scene name='85/857155/Chain_a/2'>Chain A</scene>" of "NolR".
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The 8VAC cryo-EM structure highlights how the protein repositions domains to optimize ligand engagement.
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Click on "<scene name='85/857155/Chain_b/2'>Chain B</scene>" of "NolR".
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== Disease ==
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Structural or concentration changes in HSA correlate with many pathologies:
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* '''Dimerization:''' Two alpha-helices (<scene name='85/857155/Alpha_1_and_alpha_5/1'>alpha-1 and alpha-5)</scene> from each monomer form a coiled-coil dimerization interface.
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* Hypoalbuminemia in liver disease, sepsis, nephrotic syndrome.
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* '''DNA Binding Domain:''' A triangular set of helices (<scene name='85/857155/Alpha_2_and_alpha_4/1'>alpha-2 and alpha-4</scene>) positions the recognition helix (<scene name='85/857155/Alpha3_alpha4/1'>alpha-3 and alpha-4</scene>) for interaction with the DNA major groove.
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* Glycation and oxidation in diabetes or chronic kidney disease, altering ligand affinity.
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* '''The Wing:''' A two-stranded antiparallel beta-sheet extends outward to interact with the minor groove.
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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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===DNA Binding and Recognition===
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Structural mapping enables correlation of clinical conditions with ligand-pocket geometry.
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The co-crystal structure of NolR with a 22-base pair operator sequence (<scene name='85/857155/Dna/1'>Oligo AT</scene>) reveals how the repressor recognizes its target. The NolR dimer binds to an asymmetric operator site.
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Select <scene name='85/857155/Dna_binding/1'>DNA binding</scene> to visualize the binding of NolR on oligo AT rich DNA.
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== Relevance ==
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The 8VAC structure is directly applicable to:
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* '''Major Groove:''' The alpha-4 helix of each monomer inserts deep into the major groove of the DNA.
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* Drug design – understanding pocket architecture assists affinity and specificity tuning.
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* '''Minor Groove:''' The beta-wing residues contact the minor groove.
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* PK/PD modeling – high-affinity albumin binders require dosage fine-tuning.
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* '''Electrostatics:''' The DNA-binding surface of NolR is positively charged, facilitating interaction with the phosphate backbone, while the opposite face is negatively charged.
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* Albumin-based drug delivery systems – nanoparticles and small molecules utilize albumin’s long circulation time.
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* '''DNA Bending:''' Upon binding, the DNA duplex bends approximately 16.8 degrees from an ideal B-form.
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* Biomarker interpretation – albumin concentration is essential in diagnoses and scoring systems.
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===The Gln56 Conformational Switch===
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This structure bridges clinical context and molecular understanding in a single cryo-EM model.
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A key finding of this study is the mechanism by which NolR binds to diverse operator sequences that vary at specific positions (A vs T). The authors crystallized NolR with two different DNA sequences: "Oligo AT" (consensus) and "Oligo AA" (variable).
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Click <scene name='85/857155/Gln56_switch/1'>Gln56 switch</scene> to visualize the Gln56 residues that are essential for the variable binding of NolR.
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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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* '''Consensus Binding (Oligo AT):''' In the first half-site, '''Gln56''' hydrogen bonds with Adenine 2. However, in the second half-site, the Gln56 side chain flips away from Thymine 7'.
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* Overall 3-domain organization:
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* '''Variable Binding (Oligo AA):''' When bound to the Oligo AA sequence (where T7' is replaced by A7'), '''Gln56''' undergoes a conformational switch. It rotates to form a hydrogen bond with the new Adenine base.
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<scene name="/sandbox/jhanvi/HSA_8VAC/overall/1">Domain overview</scene>
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===References===
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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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* 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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===About this Page===
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* Flexibility + domain movements:
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<!-- This section ensures you get credit -->
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<scene name="/sandbox/jhanvi/HSA_8VAC/flexibility/1">Hinge flexibility</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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== Uploaded Figures ==
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Insert your PNGs here after uploading (instructions below):
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</StructureSection>
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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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