4UC5

Neisseria Meningitidis DAH7PS-Phenylalanine regulated

4UC5 の概要

• エントリーDOI: 10.2210/pdb4uc5/pdb
• 関連するPDBエントリー: 4UCG
• 分子名称: PHOSPHO-2-DEHYDRO-3-DEOXYHEPTONATE ALDOLASE, MANGANESE (II) ION, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• 機能のキーワード: transferase, dahps shikimate pathway phenylalanine type 1a
• 由来する生物種: NEISSERIA MENINGITIDIS
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 156219.41

構造登録者

Heyes, L.C.,Lang, E.J.M.,Parker, E.J. (登録日: 2014-12-03, 公開日: 2015-11-25, 最終更新日: 2023-12-20)

主引用文献

Lang, E.J.,Heyes, L.C.,Jameson, G.B.,Parker, E.J.
Calculated Pka Variations Expose Dynamic Allosteric Communication Networks.
J.Am.Chem.Soc., 138:2036-, 2016

PubMed Abstract: Allosteric regulation of protein function, the process by which binding of an effector molecule provokes a functional response from a distal site, is critical for metabolic pathways. Yet, the way the allosteric signal is communicated remains elusive, especially in dynamic, entropically driven regulation mechanisms for which no major conformational changes are observed. To identify these dynamic allosteric communication networks, we have developed an approach that monitors the pKa variations of ionizable residues over the course of molecular dynamics simulations performed in the presence and absence of an allosteric regulator. As the pKa of ionizable residues depends on their environment, it represents a simple metric to monitor changes in several complex factors induced by binding an allosteric effector. These factors include Coulombic interactions, hydrogen bonding, and solvation, as well as backbone motions and side chain fluctuations. The predictions that can be made with this method concerning the roles of ionizable residues for allosteric communication can then be easily tested experimentally by changing the working pH of the protein or performing single point mutations. To demonstrate the method's validity, we have applied this approach to the subtle dynamic regulation mechanism observed for Neisseria meningitidis 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase, the first enzyme of aromatic biosynthesis. We were able to identify key communication pathways linking the allosteric binding site to the active site of the enzyme and to validate these findings experimentally by reestablishing the catalytic activity of allosterically inhibited enzyme via modulation of the working pH, without compromising the binding affinity of the allosteric regulator.

PubMed: 26794122
DOI: 10.1021/JACS.5B13134

実験手法

X-RAY DIFFRACTION (2.19 Å)