6p0k

Crystal structure of GDP-bound human RalA in a covalent complex with aryl sulfonyl fluoride compounds.

spinqualitylabelsall models 6p0k, resolution 1.49Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6p0k 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 1.49Å Ligands: CA, CL, GDP, NLV Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function RALA_HUMAN Multifunctional GTPase involved in a variety of cellular processes including gene expression, cell migration, cell proliferation, oncogenic transformation and membrane trafficking. Accomplishes its multiple functions by interacting with distinct downstream effectors. Acts as a GTP sensor for GTP-dependent exocytosis of dense core vesicles. Plays a role in the early stages of cytokinesis and is required to tether the exocyst to the cytokinetic furrow. The RALA-exocyst complex regulates integrin-dependent membrane raft exocytosis and growth signaling. Key regulator of LPAR1 signaling and competes with ADRBK1 for binding to LPAR1 thus affecting the signaling properties of the receptor. Required for anchorage-independent proliferation of transformed cells. Publication Abstract from PubMed Ral (Ras-like) GTPases are directly activated by oncogenic Ras GTPases. Mutant K-Ras (G12C) has enabled the development of covalent K-Ras inhibitors currently in clinical trials. However, Ral, and the overwhelming majority of mutant oncogenic K-Ras, are devoid of a druggable pocket and lack an accessible cysteine for the development of a covalent inhibitor. Here, we report that covalent bond formation by an aryl sulfonyl fluoride electrophile at a tyrosine residue (Tyr-82) inhibits guanine exchange factor Rgl2-mediated nucleotide exchange of Ral GTPase. A high-resolution 1.18-A X-ray cocrystal structure shows that the compound binds to a well-defined binding site in RalA as a result of a switch II loop conformational change. The structure, along with additional high-resolution crystal structures of several analogs in complex with RalA, confirm the importance of key hydrogen bond anchors between compound sulfone oxygen atoms and Ral backbone nitrogen atoms. Our discovery of a pocket with features found on known druggable sites and covalent modification of a bystander tyrosine residue present in Ral and Ras GTPases provide a strategy that could lead to therapeutic agent targeting oncogenic Ras mutants that are devoid of a cysteine nucleophile. Small-molecule covalent bond formation at tyrosine creates a binding site and inhibits activation of Ral GTPases.,Bum-Erdene K, Liu D, Gonzalez-Gutierrez G, Ghozayel MK, Xu D, Meroueh SO Proc Natl Acad Sci U S A. 2020 Mar 16. pii: 1913654117. doi:, 10.1073/pnas.1913654117. PMID:32179690 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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