1THL

Thermolysin complexed with a novel glutaramide derivative, n-(1-(2(r,s)-carboxy-4-phenylbutyl) cyclopentylcarbonyl)-(s)-tryptophan

1THL の概要

• エントリーDOI: 10.2210/pdb1thl/pdb
• 関連するBIRD辞書のPRD_ID: PRD_000237
• 分子名称: THERMOLYSIN, CALCIUM ION, ZINC ION, ... (5 entities in total)
• 機能のキーワード: metalloproteinase, glutaramide derivative, thermolysin, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Bacillus thermoproteolyticus
• 細胞内の位置: Secreted: P00800
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35064.59

構造登録者

Holland, D.R.,Matthews, B.W. (登録日: 1993-11-17, 公開日: 1994-01-31, 最終更新日: 2024-05-22)

主引用文献

Holland, D.R.,Barclay, P.L.,Danilewicz, J.C.,Matthews, B.W.,James, K.
Inhibition of Thermolysin and Neutral Endopeptidase 24.11 By a Novel Glutaramide Derivative; X-Ray Structure Determination of the Thermolysin-Inhibitor Complex
Biochemistry, 33:51-56, 1994

PubMed Abstract: Determination of the X-ray structure of thermolysin-inhibitor complexes has proven useful in aiding our understanding of the mode of binding of inhibitors of related, physiologically important, mammalian zinc peptidases including neutral endopeptidase EC 3.4.24.11 and angiotensin-converting enzyme. Here we describe the mode of binding to crystalline thermolysin of N-[1-(2(R,S)-carboxy-4-phenylbutyl)-cyclopentylcarbonyl]-(S) -tryptophan (CCT). CCT is an analogue of both candoxatrilat, a potent inhibitor of neutral endopeptidase 24.11, and of the 5-indanyl ester prodrug candoxatril, which is under clinical evaluation as a potential therapy for congestive heart failure. CCT differs from the previously studied N-carboxyalkyl dipeptide CLT [N-(S)-(1-carboxy-3-phenylpropyl)-(S)-leucyl-(S)-tryptophan] in several important respects. It has a highly constrained gem-cyclopentyl P1' substituent and lacks the characteristic imino nitrogen substituent of CLT. The structure determination shows that, notwithstanding the conformational influence of the gem-cyclopentyl substituent, CCT binds within the active site of thermolysin in a similar manner to CLT. Although the characteristic hydrogen bond between the imino nitrogen of CLT and thermolysin is absent in CCT, the affinities of the two inhibitors for the enzyme are virtually identical. These results illustrate the importance of considering not only those hydrogen bonds that are formed in an enzyme-ligand complex but also the other hydrogen bonds that may be lost due to desolvation of the enzyme and ligand on formation of the complex. In addition, the overall conformational demands placed upon a ligand in order to achieve receptor interaction may be critically important.

PubMed: 8286362
DOI: 10.1021/bi00167a007

実験手法

X-RAY DIFFRACTION (1.7 Å)