4IBR

Crystal structure of stabilized TEM-1 beta-lactamase variant v.13 carrying G238S/E104K mutations

4IBR の概要

• エントリーDOI: 10.2210/pdb4ibr/pdb
• 関連するPDBエントリー: 1ERO 1L7U 4IBX
• 分子名称: TEM-94 ES-beta-lactamase, CALCIUM ION, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (4 entities in total)
• 機能のキーワード: beta-lactamase, hydrolase
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29036.19

構造登録者

Dellus-Gur, E.,Toth-Petroczy, A.,Elias, M.,Tawfik, D.S. (登録日: 2012-12-09, 公開日: 2013-04-03, 最終更新日: 2024-11-06)

主引用文献

Dellus-Gur, E.,Toth-Petroczy, A.,Elias, M.,Tawfik, D.S.
What Makes a Protein Fold Amenable to Functional Innovation? Fold Polarity and Stability Trade-offs.
J.Mol.Biol., 425:2609-2621, 2013

PubMed Abstract: Protein evolvability includes two elements--robustness (or neutrality, mutations having no effect) and innovability (mutations readily inducing new functions). How are these two conflicting demands bridged? Does the ability to bridge them relate to the observation that certain folds, such as TIM barrels, accommodate numerous functions, whereas other folds support only one? Here, we hypothesize that the key to innovability is polarity--an active site composed of flexible, loosely packed loops alongside a well-separated, highly ordered scaffold. We show that highly stabilized variants of TEM-1 β-lactamase exhibit selective rigidification of the enzyme's scaffold while the active-site loops maintained their conformational plasticity. Polarity therefore results in stabilizing, compensatory mutations not trading off, but instead promoting the acquisition of new activities. Indeed, computational analysis indicates that in folds that accommodate only one function throughout evolution, for example, dihydrofolate reductase, ≥ 60% of the active-site residues belong to the scaffold. In contrast, folds associated with multiple functions such as the TIM barrel show high scaffold-active-site polarity (~20% of the active site comprises scaffold residues) and >2-fold higher rates of sequence divergence at active-site positions. Our work suggests structural measures of fold polarity that appear to be correlated with innovability, thereby providing new insights regarding protein evolution, design, and engineering.

PubMed: 23542341
DOI: 10.1016/j.jmb.2013.03.033

実験手法

X-RAY DIFFRACTION (2.2 Å)