5KDQ

Deoxyhemoglobin in Complex with an Aryloxyalkanoic acid

5KDQ の概要

• エントリーDOI: 10.2210/pdb5kdq/pdb
• 分子名称: Hemoglobin subunit alpha, Hemoglobin subunit beta, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total)
• 機能のキーワード: hemoglobin, sickle cell disease, allosteric effector, aryloxyalkanoic, oxygen transport
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 65003.67

構造登録者

Ahmed, M.H.,Omar, A.M.,Safo, M.K. (登録日: 2016-06-08, 公開日: 2016-06-22, 最終更新日: 2023-09-27)

主引用文献

Omar, A.M.,Mahran, M.A.,Ghatge, M.S.,Bamane, F.H.,Ahmed, M.H.,El-Araby, M.E.,Abdulmalik, O.,Safo, M.K.
Aryloxyalkanoic Acids as Non-Covalent Modifiers of the Allosteric Properties of Hemoglobin.
Molecules, 21:-, 2016

PubMed Abstract: Hemoglobin (Hb) modifiers that stereospecifically inhibit sickle hemoglobin polymer formation and/or allosterically increase Hb affinity for oxygen have been shown to prevent the primary pathophysiology of sickle cell disease (SCD), specifically, Hb polymerization and red blood cell sickling. Several such compounds are currently being clinically studied for the treatment of SCD. Based on the previously reported non-covalent Hb binding characteristics of substituted aryloxyalkanoic acids that exhibited antisickling properties, we designed, synthesized and evaluated 18 new compounds (KAUS II series) for enhanced antisickling activities. Surprisingly, select test compounds showed no antisickling effects or promoted erythrocyte sickling. Additionally, the compounds showed no significant effect on Hb oxygen affinity (or in some cases, even decreased the affinity for oxygen). The X-ray structure of deoxygenated Hb in complex with a prototype compound, KAUS-23, revealed that the effector bound in the central water cavity of the protein, providing atomic level explanations for the observed functional and biological activities. Although the structural modification did not lead to the anticipated biological effects, the findings provide important direction for designing candidate antisickling agents, as well as a framework for novel Hb allosteric effectors that conversely, decrease the protein affinity for oxygen for potential therapeutic use for hypoxic- and/or ischemic-related diseases.

PubMed: 27529207
DOI: 10.3390/molecules21081057

実験手法

X-RAY DIFFRACTION (2.15 Å)