4I01

Structure of the mutant Catabolite gen activator protein V140L

4I01 の概要

• エントリーDOI: 10.2210/pdb4i01/pdb
• 関連するPDBエントリー: 4HZF 4I02 4I09 4I0A 4I0B
• 分子名称: Catabolite gene activator, ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE (3 entities in total)
• 機能のキーワード: dna binding, transcription
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 51171.62

構造登録者

Pohl, E.,Townsend, P.D.,Rodgers, T.,Burnell, D.,McLeish, T.C.B.,Wilson, M.R.,Cann, M.J. (登録日: 2012-11-16, 公開日: 2013-10-30, 最終更新日: 2024-02-28)

主引用文献

Rodgers, T.L.,Townsend, P.D.,Burnell, D.,Jones, M.L.,Richards, S.A.,McLeish, T.C.,Pohl, E.,Wilson, M.R.,Cann, M.J.
Modulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors.
Plos Biol., 11:e1001651-e1001651, 2013

PubMed Abstract: Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distinct site. There is growing evidence that allosteric cooperativity can be communicated by modulation of protein dynamics without conformational change. The mechanisms, however, for communicating dynamic fluctuations between sites are debated. We provide a foundational theory for how allostery can occur as a function of low-frequency dynamics without a change in structure. We have generated coarse-grained models that describe the protein backbone motions of the CRP/FNR family transcription factors, CAP of Escherichia coli and GlxR of Corynebacterium glutamicum. The latter we demonstrate as a new exemplar for allostery without conformation change. We observe that binding the first molecule of cAMP ligand is correlated with modulation of the global normal modes and negative cooperativity for binding the second cAMP ligand without a change in mean structure. The theory makes key experimental predictions that are tested through an analysis of variant proteins by structural biology and isothermal calorimetry. Quantifying allostery as a free energy landscape revealed a protein "design space" that identified the inter- and intramolecular regulatory parameters that frame CRP/FNR family allostery. Furthermore, through analyzing CAP variants from diverse species, we demonstrate an evolutionary selection pressure to conserve residues crucial for allosteric control. This finding provides a link between the position of CRP/FNR transcription factors within the allosteric free energy landscapes and evolutionary selection pressures. Our study therefore reveals significant features of the mechanistic basis for allostery. Changes in low-frequency dynamics correlate with allosteric effects on ligand binding without the requirement for a defined spatial pathway. In addition to evolving suitable three-dimensional structures, CRP/FNR family transcription factors have been selected to occupy a dynamic space that fine-tunes biological activity and thus establishes the means to engineer allosteric mechanisms driven by low-frequency dynamics.

PubMed: 24058293
DOI: 10.1371/journal.pbio.1001651

実験手法

X-RAY DIFFRACTION (2.3 Å)