6U9B

Hsp90a NTD covalently bound to sulfonyl fluoride 5 at K58

Summary for 6U9B

• Entry DOI: 10.2210/pdb6u9b/pdb
• Related: 6U98 6U99 6U9A
• Descriptor: Heat shock protein HSP 90-alpha, 3-{[(3S)-3-({6-amino-8-[(6-iodo-2H-1,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-yl}methyl)piperidin-1-yl]methyl}benzene-1-sulfonyl fluoride (3 entities in total)
• Functional Keywords: inhibitor, lysine-targeted inhibitor, chaperone, chaperone-inhibitor complex, chaperone/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 29362.52

Authors

Cuesta, A.,Wan, X.,Taunton, J. (deposition date: 2019-09-07, release date: 2020-02-19, Last modification date: 2024-11-13)

Primary citation

Cuesta, A.,Wan, X.,Burlingame, A.L.,Taunton, J.
Ligand Conformational Bias Drives Enantioselective Modification of a Surface-Exposed Lysine on Hsp90.
J.Am.Chem.Soc., 142:3392-3400, 2020

PubMed Abstract: Targeted covalent modification of surface-exposed lysines is challenging due to their low intrinsic reactivity and high prevalence throughout the proteome. Strategies for optimizing the rate of covalent bond formation by a reversibly bound inhibitor () typically involve increasing the reactivity of the electrophile, which increases the risk of off-target modification. Here, we employ an alternative approach for increasing of a lysine-targeted covalent Hsp90 inhibitor, independent of the reversible binding affinity () or the intrinsic electrophilicity. Starting with a noncovalent ligand, we appended a chiral, conformationally constrained linker, which orients an arylsulfonyl fluoride to react rapidly and enantioselectively with Lys58 on the surface of Hsp90. Biochemical experiments and high-resolution crystal structures of covalent and noncovalent ligand/Hsp90 complexes provide mechanistic insights into the role of ligand conformation in the observed enantioselectivity. Finally, we demonstrate selective covalent targeting of cellular Hsp90, which results in a prolonged heat shock response despite concomitant degradation of the covalent ligand/Hsp90 complex. Our work highlights the potential of engineering ligand conformational constraints to dramatically accelerate covalent modification of a distal, poorly nucleophilic lysine on the surface of a protein target.

PubMed: 32009391
DOI: 10.1021/jacs.9b09684

Experimental method

X-RAY DIFFRACTION (1.75 Å)