This page describes the 3D structure and biological relevance of the human Hsp90 N-terminal domain (Hsp90N) in complex with the anticancer inhibitor SNX-2112. The structure was solved at 2.14 Å resolution (PDB ID: 6LTK) and provides detailed molecular insights into how SNX-2112 stabilizes within the ATP-binding pocket of Hsp90 to inhibit chaperone activity.
Structure
The protein in this structure represents the **N-terminal ATP-binding domain of human Hsp90**, consisting of a compact α/β fold typical of GHKL ATPases.
SNX-2112 binds deeply within the **adenine-binding cleft**, forming hydrogen bonds with key residues such as **Asp93, Leu107, Phe138, Tyr139, and Met98**.
These interactions mimic ATP and competitively block nucleotide binding.
Function
Hsp90 is an essential **ATP-dependent molecular chaperone** responsible for folding, stabilizing, and activating hundreds of client proteins, including kinases, steroid hormone receptors, and oncogenic regulators.
The N-terminal domain performs:
- ATP binding and hydrolysis
- Conformational switching required for chaperone cycling
- Recruitment and regulation of client proteins
SNX-2112 inhibits this critical ATP-dependent function.
Disease relevance
Hsp90 is heavily upregulated in cancer, where it stabilizes oncogenic clients such as:
- **Akt**
- **Raf-1**
- **HER2**
- **EGFR**
By inhibiting Hsp90, SNX-2112 disrupts these signaling pathways—leading to **apoptosis, cell-cycle arrest, and reduced proliferation**, especially in **non-small cell lung cancer (NSCLC)** cell lines (A549, H1299).
Relevance
Hsp90 inhibitors are important anticancer therapeutics.
The 6LTK structure aids in:
- Understanding inhibitor binding specificity
- Designing improved SNX-2112 analogs
- Creating next-generation Hsp90-targeted drugs with reduced toxicity
Structural highlights
- **Deep hydrophobic binding pocket** with aromatic stacking
- **Hydrogen bonds** between inhibitor heterocycles and Asp93
- **π–π interactions** with Phe138 and Tyr139
- **Tight cavity occupancy**—explaining high binding affinity
Key structural insights
1. SNX-2112 strongly mimics ATP’s adenine interactions → competitive inhibition.
2. The inhibitor’s rigid aromatic scaffold fits precisely into the pocket → high potency.
3. The structure explains why SNX-2112 has selectivity for Hsp90 over related GHKL ATPases.
4. These atomic details provide a platform for structure-guided cancer drug development.
Images
(Add your uploaded PyMOL images here)
3D Scenes (interactive)
Methods / Data sources
- PDB ID: **6LTK**
- Resolution: **2.14 Å**
- Technique: **X-ray crystallography**
- Expression system: **E. coli**
- Software: Proteopedia, PyMOL, Jmol
References
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PyMOL Scripts
1. Overall structure
fetch 6ltk, async=0
hide everything
show cartoon, chain A
color lightblue, chain A
show sticks, resn SNX
color yellow, resn SNX
bg white
2. Binding pocket close-up
fetch 6ltk, async=0
hide everything
show cartoon, chain A
zoom resn SNX
show sticks, resn SNX
select pocket, byres (resn SNX around 4)
show sticks, pocket
util.cbc pocket
bg white
</StructureSection>
