4EJD

HIV Protease (PR) dimer in closed form with pepstatin in active site and fragment 1F1 in the outside/top of flap

4EJD の概要

• エントリーDOI: 10.2210/pdb4ejd/pdb
• 関連するPDBエントリー: 4EJ8 4EJK 4EJL
• 関連するBIRD辞書のPRD_ID: PRD_000557
• 分子名称: Protease, pepstatin, BETA-MERCAPTOETHANOL, ... (6 entities in total)
• 機能のキーワード: apo protease, allostery, fragment binding, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Human immunodeficiency virus 1; 詳細
• 細胞内の位置: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P12499
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 22837.21

構造登録者

Tiefenbrunn, T.,Stout, C.D. (登録日: 2012-04-06, 公開日: 2013-05-01, 最終更新日: 2014-02-19)

主引用文献

Tiefenbrunn, T.,Forli, S.,Baksh, M.M.,Chang, M.W.,Happer, M.,Lin, Y.C.,Perryman, A.L.,Rhee, J.K.,Torbett, B.E.,Olson, A.J.,Elder, J.H.,Finn, M.G.,Stout, C.D.
Small molecule regulation of protein conformation by binding in the Flap of HIV protease.
Acs Chem.Biol., 8:1223-1231, 2013

PubMed Abstract: The fragment indole-6-carboxylic acid (1F1), previously identified as a flap site binder in a fragment-based screen against HIV protease (PR), has been cocrystallized with pepstatin-inhibited PR and with apo-PR. Another fragment, 3-indolepropionic acid (1F1-N), predicted by AutoDock calculations and confirmed in a novel inhibition of nucleation crystallization assay, exploits the same interactions in the flap site in two crystal structures. Both 1F1 and 1F1-N bind to the closed form of apo-PR and to pepstatin:PR. In solution, 1F1 and 1F1-N raise the Tm of apo-PR by 3.5-5 °C as assayed by differential scanning fluorimetry (DSF) and show equivalent low-micromolar binding constants to both apo-PR and pepstatin:PR, assayed by backscattering interferometry (BSI). The observed signal intensities in BSI are greater for each fragment upon binding to apo-PR than to pepstatin-bound PR, consistent with greater conformational change in the former binding event. Together, these data indicate that fragment binding in the flap site favors a closed conformation of HIV PR.

PubMed: 23540839
DOI: 10.1021/cb300611p

実験手法

X-RAY DIFFRACTION (1.103 Å)