6u99

Hsp90a NTD covalently bound to sulfonyl fluoride probe 1 at K58

spinqualitylabelsall models 6u99, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6u99 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.6Å Ligands: Q2J Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function HS90A_HUMAN Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. Publication Abstract from PubMed 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 (kinact) typically involve increasing the reactivity of the electrophile, which increases the risk of off-target modification. Here, we employ an alternative approach for increasing kinact of a lysine-targeted covalent Hsp90 inhibitor, independent of the reversible binding affinity (Ki) 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. Ligand Conformational Bias Drives Enantioselective Modification of a Surface-Exposed Lysine on Hsp90.,Cuesta A, Wan X, Burlingame AL, Taunton J J Am Chem Soc. 2020 Feb 3. doi: 10.1021/jacs.9b09684. PMID:32009391 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Heat Shock Protein structures

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