8oy1
Structure of the human Guanine Nucleotide-Binding Protein G(K) Subunit Alpha
Structural highlights
DiseaseGNAI3_HUMAN Defects in GNAI3 are the cause of auriculocondylar syndrome 1 (ARCND1) [MIM:602483. ARCND1 is an autosomal dominant craniofacial malformation syndrome characterized by variable mandibular anomalies, including mild to severe micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic ear malformation that consists of separation of the lobule from the external ear, giving the appearance of a question mark (question-mark ear). Other frequently described features include prominent cheeks, cupped and posteriorly rotated ears, preauricular tags, and microstomia.[1] FunctionGNAI3_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. G(k) is the stimulatory G protein of receptor-regulated K(+) channels. The active GTP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[2] Publication Abstract from PubMedThe small molecule IGGi-11 targets Galphai subunits of heterotrimeric guanine nucleotide-binding proteins. Galpha subunits are activated by G-protein-coupled receptors in response to extracellular stimuli by accelerating the exchange of GDP for GTP, but they are also activated by intracellular proteins like GIV, of which elevated levels correlate with increased cell migration and cancer metastasis. IGGi-11 disrupts the interaction of Galphai proteins with GIV and inhibits pro-invasive traits of metastatic breast cancer cells without interfering with GPCR signaling. IGGi-11 is a competitive inhibitor but binds Galphai3 with a 10-fold lower affinity than GIV. To guide the design of higher affinity inhibitors, we aimed at obtaining high-resolution structural data on the complex. To facilitate its crystallization, we have removed the most flexible residues at the chain ends of Galphai3, identified by NMR. While Galphai3 crystals grown with excess IGGi-11 did not show the bound compound, computational docking and molecular dynamics simulations identified the interactions driving the molecular recognition. This approach revealed heterogeneous binding due to the symmetry of IGGi-11 chemical structure and to the elongated shape and flexibility of the binding site. Our results suggest that chemical modifications breaking IGGi-11 symmetry might yield inhibitors with higher affinity and potential as antimetastatic drugs. Integrated NMR-crystallography-computational approach for molecular recognition studies of human Galphai3 protein by a small molecule inhibitor.,Ferreras-Gutierrez M, Minguez-Toral M, Ibanez de Opakua A, Martin-Santamaria S, Garcia-Marcos M, Medrano FJ, Blanco FJ Int J Biol Macromol. 2024 Dec 18;290:138977. doi: 10.1016/j.ijbiomac.2024.138977. PMID:39706421[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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