4G1Q

Crystal structure of HIV-1 reverse transcriptase (RT) in complex with Rilpivirine (TMC278, Edurant), a non-nucleoside rt-inhibiting drug

Summary for 4G1Q

• Entry DOI: 10.2210/pdb4g1q/pdb
• Related: 1S6Q 1SV5 2IC3 2ZD1 2ZE2 3BGR 3DLK 3V81
• Descriptor: Reverse transcriptase/ribonuclease H, p51 RT, 4-{[4-({4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile, ... (7 entities in total)
• Functional Keywords: p51/p66, hetero dimer, nnrti, nonnucleoside inhibitor, aids, hiv, r278474, diarylpyrimidine, dapy, dna recombination, rna-directed dna polymerase, dna polymerase, endonuclease, hydrolase, multifunctional enzyme, transferase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Human immunodeficiency virus type 1 (HIV-1); More
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03366 P03366
• Total number of polymer chains: 2
• Total formula weight: 115306.17

Authors

Bauman, J.D.,Patel, D.,Das, K.,Arnold, E. (deposition date: 2012-07-11, release date: 2013-02-06, Last modification date: 2023-09-13)

Primary citation

Kuroda, D.G.,Bauman, J.D.,Challa, J.R.,Patel, D.,Troxler, T.,Das, K.,Arnold, E.,Hochstrasser, R.M.
Snapshot of the equilibrium dynamics of a drug bound to HIV-1 reverse transcriptase.
Nat Chem, 5:174-181, 2013

PubMed Abstract: The anti-AIDS drug rilpivirine undergoes conformational changes to bind HIV-1 reverse transcriptase (RT), which is an essential enzyme for the replication of HIV. These changes allow it to retain potency against mutations that otherwise would render the enzyme resistant. Here we report that water molecules play an essential role in this binding process. Femtosecond experiments and theory expose the molecular level dynamics of rilpivirine bound to HIV-1 RT. Two nitrile substituents, one on each arm of the drug, are used as vibrational probes of the structural dynamics within the binding pocket. Two-dimensional vibrational echo spectroscopy reveals that one nitrile group is unexpectedly hydrogen-bonded to a mobile water molecule, not identified in previous X-ray structures. Ultrafast nitrile-water dynamics are confirmed by simulations. A higher (1.51 Å) resolution X-ray structure also reveals a water-drug interaction network. Maintenance of a crucial anchoring hydrogen bond may help retain the potency of rilpivirine against pocket mutations despite the structural variations they cause.

PubMed: 23422558
DOI: 10.1038/nchem.1559

Experimental method

X-RAY DIFFRACTION (1.51 Å)