2NPH

Crystal structure of HIV1 protease in situ product complex

2NPH の概要

• エントリーDOI: 10.2210/pdb2nph/pdb
• 関連するPDBエントリー: 1G6L 1LV1
• 分子名称: PROTEASE RETROPEPSIN, tetrapeptide fragment, pentapeptide fragment, ... (4 entities in total)
• 機能のキーワード: anti-parallel beta sheet, hydrolase
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 22625.58

構造登録者

Hosur, M.V.,Das, A.,Prashar, V. (登録日: 2006-10-27, 公開日: 2006-12-19, 最終更新日: 2023-12-27)

主引用文献

Das, A.,Prashar, V.,Mahale, S.,Serre, L.,Ferrer, J.-L.,Hosur, M.V.
Crystal structure of HIV-1 protease in situ product complex and observation of a low-barrier hydrogen bond between catalytic aspartates
Proc.Natl.Acad.Sci.Usa, 103:18464-18469, 2006

PubMed Abstract: HIV-1 protease is an effective target for designing drugs against AIDS, and structural information about the true transition state and the correct mechanism can provide important inputs. We present here the three-dimensional structure of a bi-product complex between HIV-1 protease and the two cleavage product peptides AETF and YVDGAA. The structure, refined against synchrotron data to 1.65 A resolution, shows the occurrence of the cleavage reaction in the crystal, with the product peptides still held in the enzyme active site. The separation between the scissile carbon and nitrogen atoms is 2.67 A, which is shorter than a normal van der Waal separation, but it is much longer than a peptide bond length. The substrate is thus in a stage just past the G'Z intermediate described in Northrop's mechanism [Northrop DB (2001) Acc Chem Res 34:790-797]. Because the products are generated in situ, the structure, by extrapolation, can give insight into the mechanism of the cleavage reaction. Both oxygens of the generated carboxyl group form hydrogen bonds with atoms at the catalytic center: one to the OD2 atom of a catalytic aspartate and the other to the scissile nitrogen atom. The latter hydrogen bond may have mediated protonation of scissile nitrogen, triggering peptide bond cleavage. The inner oxygen atoms of the catalytic aspartates in the complex are 2.30 A apart, indicating a low-barrier hydrogen bond between them at this stage of the reaction, an observation not included in Northrop's proposal. This structure forms a template for designing mechanism-based inhibitors.

PubMed: 17116869
DOI: 10.1073/pnas.0605809103

実験手法

X-RAY DIFFRACTION (1.65 Å)