1XHM

The Crystal Structure of a Biologically Active Peptide (SIGK) Bound to a G Protein Beta:Gamma Heterodimer

Summary for 1XHM

• Entry DOI: 10.2210/pdb1xhm/pdb
• Related: 1A0R 1GG2 1OMW 1TBG
• Descriptor: Guanine nucleotide-binding protein G(I)/G(S)/G(T) beta subunit 1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) gamma-2 subunit, SIGK Peptide, ... (4 entities in total)
• Functional Keywords: wd40 repeat, beta-propeller, protein-peptide complex, signaling protein
• Biological source: Bos taurus (cattle); More
• Cellular location: Cell membrane; Lipid-anchor; Cytoplasmic side (Potential): P63212
• Total number of polymer chains: 3
• Total formula weight: 47795.87

Authors

Davis, T.L.,Bonacci, T.M.,Smrcka, A.V.,Sprang, S.R. (deposition date: 2004-09-20, release date: 2005-08-09, Last modification date: 2023-08-23)

Primary citation

Davis, T.L.,Bonacci, T.M.,Sprang, S.R.,Smrcka, A.V.
Structural and Molecular Characterization of a Preferred Protein Interaction Surface on G Protein betagamma Subunits.
Biochemistry, 44:10593-10604, 2005

PubMed Abstract: G protein betagamma subunits associate with many binding partners in cellular signaling cascades. In previous work, we used random-peptide phage display screening to identify a diverse family of peptides that bound to a common surface on Gbetagamma subunits and blocked a subset of Gbetagamma effectors. Later studies showed that one of the peptides caused G protein activation through a novel Gbetagamma-dependent, nucleotide exchange-independent mechanism. Here we report the X-ray crystal structure of Gbeta(1)gamma(2) bound to this peptide, SIGK (SIGKAFKILGYPDYD), at 2.7 A resolution. SIGK forms a helical structure that binds the same face of Gbeta(1) as the switch II region of Galpha. The interaction interface can be subdivided into polar and nonpolar interfaces that together contain a mixture of binding determinants that may be responsible for the ability of this surface to recognize multiple protein partners. Systematic mutagenic analysis of the peptide-Gbeta(1) interface indicates that distinct sets of amino acids within this interface are required for binding of different peptides. Among these unique amino acid interactions, specific electrostatic binding contacts within the polar interface are required for peptide-mediated subunit dissociation. The data provide a mechanistic basis for multiple target recognition by Gbetagamma subunits with diverse functional interactions within a common interface and suggest that pharmacological targeting of distinct regions within this interface could allow for selective manipulation of Gbetagamma-dependent signaling pathways.

PubMed: 16060668
DOI: 10.1021/bi050655i

Experimental method

X-RAY DIFFRACTION (2.7 Å)