台大趙治宇教授榮獲Nature雜誌邀請擔任Scientific Reports的編輯委員

日期:2021/09/19   IAE 報導

賀台大趙治宇教授榮獲Nature雜誌邀請擔任Scientific Reports的編輯委員

賀趙治宇教授率領台大團隊研究高攜氧血紅蛋白結構, 獲得突破性之重要研究成果血紅蛋白攜氧動態協同效應之冷凍電鏡結構研究
"Structural basis for cooperative oxygen binding and bracelet-assisted assembly of Lumbricus terrestris hemoglobin"  
刊登於Nature雜誌的 Scientific Reports , 可望對缺氧急性重症之醫療帶來新曙光。

物理系趙治宇教授研究成果分享

研究高攜氧血紅蛋白之結構與協同效應

物理系趙治宇教授研究成果分享「研究高攜氧血紅蛋白之結構與協同效應」, 成果登於Nature雜誌的Scientific Report,可望對缺氧型急性重症之醫療帶來新的曙光。

含鐵的血紅蛋白是血液中用來輸送氧氣的重要蛋白質。之所以它能攜帶並釋放氧氣到特定的器官,在於它獨特的攜氧協同效應。在眾多的物種當中,蚯蚓的血紅蛋白有著最佳的攜氧能力,不只是因為它擁有巨大的分子量(144個heme group),也是因為它異於其他物種異常高的協同結合能力。科學家認為它的攜氧機制和脊椎動物與大部分的無脊椎動物大相逕庭,可惜的是,因為缺少在不同生理狀態的結構比較,科學家對於其協同攜氧機制仍然所知甚少。

趙治宇教授研究團隊利用冷凍穿透式電子顯微術,搭配三維重建與分子動態模擬,解出近原子級解析之蚯蚓血紅蛋白之結構,首度發現了此蛋白之攜氧協同效應之變構機制,及首度瞭解此蛋白其如何形成之組裝機制,此為目前已知最高解析之血紅蛋白原態(native state)結構,此成果發表在Nature雜誌的Scientific Reports。

我們針對不同生理狀態的結構分析顯示,在含氧和一氧化碳的狀態之間有顯著的結構差異,為了呈現完整的協同結合功能,蚯蚓血紅蛋白需要heme group附近三級和四級結構改變以及藉由不同接觸點所帶動的整體外擴。此結果顯示了蚯蚓血紅蛋白相較於其他物種更加複雜的協同攜氧機制。我們針對其變構機制提出了一分子模型(圖)。

 

1. 首先當氧氣結合上了含鐵的heme group,使得鐵原子有一位移,藉由和近端histidine的交互作用,牽動了helix-F。

2. 此結構變化透過不同接觸點傳遞到L1 linker的β-barrel domain並推動它使之外擴。

3. 由於β-barrel domain位於上下雙層結構的接觸區域,因此帶動了血紅蛋白有一整體的結構膨脹。

 

  本研究成果提供對血紅蛋白分子結構之深入瞭解,由於此蛋白之高攜氧率(人類之36-144倍)與低自氧化速率等特性,其結構資訊將成為後續臨床上人造血與輸血醫學之重要基石,透過瞭解其攜氧機制,我們可以改良人造血液氧氣運輸的效率,為新一代人造血之開發研究提供了一大契機。

 

  趙教授團隊未來將針對人體局部急性重症之患者進行急救藥物之開發,因將此極高攜氧量之血紅素注入急性肺衰竭或急性腦中風/栓塞的患者,藉由其高協同效應之特性快速釋放氧氣到缺氧組織,可使細胞不致於因太早缺氧而死亡,目前正與本校醫院神經內科、胸腔科和血液腫瘤科的醫師申請第一期phase 1的人體試驗(IRB),同時趙教授也正與兩家藥廠洽談進一步合作開發這類急救性藥物之可能性,期待對缺氧型急性重症之醫療帶來新的曙光。

圖 血紅蛋白之協同變構機制

NTU HIGHLIGHTS OCTOBER 2015

RESEARCH ACHIEVEMENTS

Earthworm Hemoglobin Shows Promise for Development of Artificial Blood

A team of researchers led by Department of Physics Prof. Chih-Yu Chao has captured the most detailed high-resolution images of the structure of hemoglobin in its native oxygenated state.  This valuable information is expected to facilitate the development of new life-saving artificial blood and emergency pharmaceuticals.  Reflecting the significance of these first-ever images, the team’s results were published in Nature’s online journal Scientific Reports in April.

 

Through the use of cryo-electron microscopy coupled with image processing and 3D-reconstruction technology, Prof. Chao and his team were able to produce near-atomic resolution images of the complete structure of Lumbricus terrestris hemoglobin in its oxygenated form.   They then used molecular dynamic simulation to compare the structural differences in this special type of hemoglobin when it binds with either carbon monoxide or oxygen.  This revealed for the first time the allosteric effect of cooperative oxygen binding in this protein, which allowed the team to provide the first explanation of its assembly mechanism.

 

Just who is this Lumbricus terrestris and what makes its hemoglobin so important?  It’s none other than your friendly earthworm, and it turns out that this mud-loving creature possesses a giant hemoglobin protein characterized by the exceptional rate at which it binds with oxygen (36 to 144 times that of human hemoglobin) as well as its high resistance to oxidation.

 

The deeper understanding of this hemoglobin’s molecular structure provided by Prof. Chao’s team shows promise as a foundation for future clinical trials aimed at the development of artificial blood and transfusion medicine.  By better understanding its oxygen binding mechanism, scientists might be able to use the earthworm’s unique hemoglobin as an oxygen carrier to boost the efficiency of artificial blood in transporting oxygen.

 

The team plans to use Lumbricus terrestris hemoglobin for the development of emergency pharmaceuticals targeting acute pulmonary failure and stroke patients.  It has joined forces with doctors at NTU Hospital in applying for authorization to carry out phase-one human clinical trials.  Taking advantage of the hemoglobin’s high cooperative oxygen binding capacity, the researchers intend to inject it into patients to quickly release oxygen to oxygen-deprived tissue and prevent cells from dying.  Prof. Chao is currently holding talks with two pharmaceutical firms concerning the feasibility of cooperating on the development of this type of emergency drug.