4U7Q

Structure of wild-type HIV protease in complex with photosensitive inhibitor PDI-6

Summary for 4U7Q

• Entry DOI: 10.2210/pdb4u7q/pdb
• Related: 4U7V
• Descriptor: V-1 protease, N~2~-({[7-(diethylamino)-2-oxo-2H-chromen-4-yl]methoxy}carbonyl)-N-[(2S,4S,5S)-4-hydroxy-1,6-diphenyl-5-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}hexan-2-yl]-L-valinamide (3 entities in total)
• Functional Keywords: hiv-1, viral protease, aspartic protease, inhibition, hydrolase
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22407.58

Authors

Pachl, P.,Rezacova, P.,Schimer, J. (deposition date: 2014-07-31, release date: 2015-03-25, Last modification date: 2023-12-20)

Primary citation

Schimer, J.,Pavova, M.,Anders, M.,Pachl, P.,Sacha, P.,Cigler, P.,Weber, J.,Majer, P.,Rezacova, P.,Krausslich, H.G.,Muller, B.,Konvalinka, J.
Triggering HIV polyprotein processing by light using rapid photodegradation of a tight-binding protease inhibitor.
Nat Commun, 6:6461-6461, 2015

PubMed Abstract: HIV protease (PR) is required for proteolytic maturation in the late phase of HIV replication and represents a prime therapeutic target. The regulation and kinetics of viral polyprotein processing and maturation are currently not understood in detail. Here we design, synthesize, validate and apply a potent, photodegradable HIV PR inhibitor to achieve synchronized induction of proteolysis. The compound exhibits subnanomolar inhibition in vitro. Its photolabile moiety is released on light irradiation, reducing the inhibitory potential by 4 orders of magnitude. We determine the structure of the PR-inhibitor complex, analyze its photolytic products, and show that the enzymatic activity of inhibited PR can be fully restored on inhibitor photolysis. We also demonstrate that proteolysis of immature HIV particles produced in the presence of the inhibitor can be rapidly triggered by light enabling thus to analyze the timing, regulation and spatial requirements of viral processing in real time.

PubMed: 25751579
DOI: 10.1038/ncomms7461

Experimental method

X-RAY DIFFRACTION (1.7 Å)