1U2B

Triglycine variant of the Grp1 Pleckstrin Homology Domain unliganded

Summary for 1U2B

• Entry DOI: 10.2210/pdb1u2b/pdb
• Related: 1U27 1U29
• Descriptor: Cytohesin 3, SULFATE ION (3 entities in total)
• Functional Keywords: ph domain, lipid binding, phosphoinositides, lipid binding protein
• Biological source: Mus musculus (house mouse)
• Cellular location: Cell membrane (By similarity): O08967
• Total number of polymer chains: 1
• Total formula weight: 16451.57

Authors

Cronin, T.C.,DiNitto, J.P.,Czech, M.P.,Lambright, D.G. (deposition date: 2004-07-16, release date: 2005-02-01, Last modification date: 2023-08-23)

Primary citation

Cronin, T.C.,DiNitto, J.P.,Czech, M.P.,Lambright, D.G.
Structural determinants of phosphoinositide selectivity in splice variants of Grp1 family PH domains
Embo J., 23:3711-3720, 2004

PubMed Abstract: The pleckstrin homology (PH) domains of the homologous proteins Grp1 (general receptor for phosphoinositides), ARNO (Arf nucleotide binding site opener), and Cytohesin-1 bind phosphatidylinositol (PtdIns) 3,4,5-trisphosphate with unusually high selectivity. Remarkably, splice variants that differ only by the insertion of a single glycine residue in the beta1/beta2 loop exhibit dual specificity for PtdIns(3,4,5)P(3) and PtdIns(4,5)P(2). The structural basis for this dramatic specificity switch is not apparent from the known modes of phosphoinositide recognition. Here, we report crystal structures for dual specificity variants of the Grp1 and ARNO PH domains in either the unliganded form or in complex with the head groups of PtdIns(4,5)P(2) and PtdIns(3,4,5)P(3). Loss of contacts with the beta1/beta2 loop with no significant change in head group orientation accounts for the significant decrease in PtdIns(3,4,5)P(3) affinity observed for the dual specificity variants. Conversely, a small increase rather than decrease in affinity for PtdIns(4,5)P(2) is explained by a novel binding mode, in which the glycine insertion alleviates unfavorable interactions with the beta1/beta2 loop. These observations are supported by a systematic mutational analysis of the determinants of phosphoinositide recognition.

PubMed: 15359279
DOI: 10.1038/sj.emboj.7600388

Experimental method

X-RAY DIFFRACTION (1.8 Å)