Pan‐HSP90 ligand binding reveals isoform‐specific differences in plasticity and water networks

Isoforms of heat shock protein 90 (HSP90) fold oncoproteins that facilitate all 10 hallmarks of cancer. However, its promise as a therapeutic target remains unfulfilled as there is still no FDA‐approved drug targeting HSP90 in disease. Among the reasons hindering progress are side effects caused by...

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Bibliographic Details
Published in:Protein science Vol. 32; no. 5; pp. e4629 - n/a
Main Authors: Stachowski, Timothy R., Nithianantham, Stanley, Vanarotti, Murugendra, Lopez, Karlo, Fischer, Marcus
Format: Journal Article
Language:English
Published: Hoboken, USA John Wiley & Sons, Inc 01.05.2023
Wiley Subscription Services, Inc
Subjects:
Antineoplastic Agents - chemistry
Binding
conformational flexibility
Heat shock proteins
HSP90 Heat-Shock Proteins - chemistry
Hsp90 isoforms
Hsp90 protein
Humans
Isoforms
ligand binding
Ligands
pan‐Hsp90 inhibitors
Protein Binding
Protein Conformation
Protein folding
Protein Isoforms - chemistry
Proteins
Side effects
Therapeutic targets
water networks
Hsp90 isoforms
conformational flexibility
pan-Hsp90 inhibitors
water networks
ligand binding
ISSN:0961-8368, 1469-896X, 1469-896X
Online Access:Get full text
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Summary:Isoforms of heat shock protein 90 (HSP90) fold oncoproteins that facilitate all 10 hallmarks of cancer. However, its promise as a therapeutic target remains unfulfilled as there is still no FDA‐approved drug targeting HSP90 in disease. Among the reasons hindering progress are side effects caused by pan‐HSP90 inhibition. Selective targeting of the four isoforms is challenging due to high sequence and structural similarity. Surprisingly, while decades of drug discovery efforts have produced almost 400 human HSP90 structures, no single ligand has been structurally characterized across all four human isoforms to date, which could reveal structural differences to achieve selectivity. To better understand the HSP90 landscape relevant for ligand binding and design we take a three‐pronged approach. First, we solved the first complete set of structures of a single ligand bound to all four human isoforms. This enabled a systematic comparison of how side‐chains and water networks respond to ligand binding across isoforms. Second, we expanded our analysis to publicly available, incomplete isoform‐ligand series with distinct ligand chemistry. This highlighted general trends of protein and water mobility that differ among isoforms and impact ligand binding. Third, we further probed the Hsp90α conformational landscape for accommodating a congeneric series containing the purine scaffold common to HSP90 inhibitors. This revealed how minor ligand modifications flip ligand poses and perturb water and protein conformations. Taken together, this work illustrates how a systematic approach can shed new light on an “old” target and reveal hidden isoform‐specific accommodations of congeneric ligands that may be exploited in ligand discovery and design. PDB Code(s): 7ULJ, 7ULL and 7ULK;
Bibliography:John Kuriyan
Review Editor
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Review Editor: John Kuriyan
ISSN:0961-8368
1469-896X
1469-896X
DOI:10.1002/pro.4629