5ZB4

Crystal structure of thymidylate kinase in complex with ADP and TMP from thermus thermophilus HB8

5ZB4 の概要

• エントリーDOI: 10.2210/pdb5zb4/pdb
• 分子名称: Thymidylate kinase, ADENOSINE-5'-DIPHOSPHATE, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: nmp kinase, transferase
• 由来する生物種: Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 46225.43

構造登録者

Chaudhary, S.K.,Jeyakanthan, J.,Sekar, K. (登録日: 2018-02-09, 公開日: 2018-12-19, 最終更新日: 2023-11-22)

主引用文献

Chaudhary, S.K.,Iyyappan, Y.,Elayappan, M.,Jeyakanthan, J.,Sekar, K.
Insights into product release dynamics through structural analyses of thymidylate kinase.
Int. J. Biol. Macromol., 123:637-647, 2018

PubMed Abstract: Several studies on enzyme catalysis have pointed out that the product release event could be a rate limiting step. In this study, we have compared the release event of two products, Adenosine di-phosphate (ADP) and Thymidine di-phosphate (TDP) from the active-site of human and Thermus thermophilus thymidine mono-phosphate kinase (TMPK), referred to as hTMPK and ttTMPK, respectively. TMPK catalyses the conversion of Thymidine mono-phosphate (TMP) to TDP using ATP as phosphoryl donor in the presence of Mg ion. Most of the earlier studies on this enzyme have focused on understanding substrate binding and catalysis, but the critical product release event remains elusive. Competitive binding experiments of the substrates and the products using ttTMPK apo crystals have indicated that the substrate (TMP) can replace the bound product (TDP), even in the presence of an ADP molecule. Further, the existing random accelerated molecular dynamics (RAMD) simulation program was modified to study the release of both the products simultaneously from the active site. The RAMD simulations on product-bound structures of both ttTMPK and hTMPK, revealed that while several exit patterns of the products are permissible, the sequential exit mode is the most preferred pattern for both ttTMPK and hTMPK enzymes. Additionally, the product release from the hTMPK was found to be faster and more directional as compared to ttTMPK. Structural investigation revealed that the critical changes in the residue composition in the LID-region of ttTMPK and hTMPK have an effect on the product release and can be attributed to the observed differences during product release event. Understanding of these dissimilarities is of considerable utility in designing potent inhibitors or prodrugs that can distinguish between eukaryotic and prokaryotic homologues of thymidylate kinase.

PubMed: 30447376
DOI: 10.1016/j.ijbiomac.2018.11.025

実験手法

X-RAY DIFFRACTION (1.92 Å)