Promiscuous Binding at the Crossroads of Numerous Cancer Pathways: Insight from the Binding of Glutaminase Interacting Protein with Glutaminase L

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• 作者：David L. Zoetewey ; Mohiuddin Ovee ; Monimoy Banerjee ; Rajagopalan Bhaskaran ; Smita Mohanty
• 刊名：Biochemistry
• 出版年：2011
• 出版时间：May 3, 2011
• 年：2011
• 卷：50
• 期：17
• 页码：3528-3539
• 全文大小：1120K
• 年卷期：v.50,no.17(May 3, 2011)
• ISSN：1520-4995

文摘

The glutaminase interacting protein (GIP) is composed of a single PDZ domain that interacts with a growing list of partner proteins, including glutaminase L, that are involved in a number of cell signaling and cancer pathways. Therefore, GIP makes a good target for structure-based drug design. Here, we report the solution structures of both free GIP and GIP bound to the C-terminal peptide analogue of glutaminase L. This is the first reported nuclear magnetic resonance structure of GIP in a complex with one of its binding partners. Our analysis of both free GIP and GIP in a complex with the glutaminase L peptide provides important insights into how a promiscuous binding domain can have affinity for multiple binding partners. Through a detailed chemical shift perturbation analysis and backbone dynamics studies, we demonstrate here that the binding of the glutaminase L peptide to GIP is an allosteric event. Taken together, the insights reported here lay the groundwork for the future development of a specific inhibitor for GIP.