2W13

High-resolution crystal structure of the P-I snake venom metalloproteinase BaP1 in complex with a peptidomimetic: insights into inhibitor binding

2W13 の概要

• エントリーDOI: 10.2210/pdb2w13/pdb
• 関連するPDBエントリー: 1ND1 2W12 2W14 2W15
• 分子名称: ZINC METALLOPROTEINASE BAP1, ZINC ION, (2R,3R)-N^1^-[(1S)-2,2-DIMETHYL-1-(METHYLCARBAMOYL)PROPYL]-N^4^-HYDROXY-2-(2-METHYLPROPYL)-3-{[(1,3-THIAZOL-2-YLCARBONYL)AMINO]METHYL}BUTANEDIAMIDE, ... (6 entities in total)
• 機能のキーワード: hydrolase inhibitor complex, metzincin, chemotaxis, adamalysins, endopeptidase, metal-binding, zinc-depending, metalloprotease, metalloproteinase-inhibitor complex, zinc, toxin, secreted, protease, hydrolase, p-i snake venom metalloproteinase, alpha-beta proteins, matrixmetalloproteinase, tumor necrosis factor alpha converting enzyme, pyrrolidone carboxylic acid, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: BOTHROPS ASPER (TERCIOPELO)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23594.00

構造登録者

Lingott, T.J.,Schleberger, C.,Gutierrez, J.M.,Merfort, I. (登録日: 2008-10-14, 公開日: 2009-06-16, 最終更新日: 2024-10-16)

主引用文献

Lingott, T.J.,Schleberger, C.,Gutierrez, J.M.,Merfort, I.
High-Resolution Crystal Structure of the Snake Venom Metalloproteinase Bap1 Complexed with a Peptidomimetic: Insight Into Inhibitor Binding.
Biochemistry, 48:6166-, 2009

PubMed Abstract: BaP1, a zinc-dependent endopeptidase belonging to the P-I class of snake venom metalloproteinases, exerts multiple tissue-damaging activities, leading to hemorrhage, myonecrosis, dermonecrosis, blistering, and edema. Interestingly, this metalloproteinase shows a high degree of structural homology with the catalytic domain of human adamalysins and matrix metalloproteinases, especially at the strictly conserved zinc binding motif and the so-called Met turn. This highlights BaP1 as an interesting model concerning inhibitor design for several medicinally important metalloproteinases, such as tumor necrosis factor alpha converting enzyme. Here, we report the first crystal structure of BaP1 complexed with a peptidomimetic inhibitor. Suitable crystals were obtained at four different pH values (4.6, 6.5, 7.5, and 8.0), and four high-resolution structures (1.46, 1.14, 1.08, and 1.05 A) were established. These structures and the detailed analysis of the structure-activity relationship of the bound inhibitor form a basis for the design of potent BaP1 inhibitors. The latter can be used for the treatment of local pathological effects caused by snake bites, mainly due to metalloproteinases such as BaP1. Besides, the high-resolution structure is an excellent starting point for the rational development of inhibitors for human metalloproteinases. The finding of a flexible loop region may have a great impact on further studies as to date little is known about the structural dependencies of the hemorrhagic activity of snake venom metalloproteinases.

PubMed: 19485419
DOI: 10.1021/BI9002315

実験手法

X-RAY DIFFRACTION (1.14 Å)