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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)

• Overall Hsp90N–SNX-2112 complex
• Binding pocket close-up

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

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