Human immunodeficiency virus 1 (HIV-1) infection is a global health issue since neither\na cure nor a vaccine is available. However, the highly active antiretroviral therapy (HAART)\nhas improved the life expectancy for patients with acquired immunodeficiency syndrome (AIDS).\nNucleoside reverse transcriptase inhibitors (NRTIs) are in almost all HAART and target reverse\ntranscriptase (RT), an essential enzyme for the virus. Even though NRTIs are highly effective,\nthey have limitations caused by RT resistance. The main mechanisms of RT resistance to NRTIs\nare discrimination and excision. Understanding the molecular mechanisms for discrimination and\nexcision are essential to develop more potent and selective NRTIs. Using protein X-ray crystallography,\nwe determined the first crystal structure of RT in its post-catalytic state in complex with emtricitabine,\n(-)FTC or stavudine (d4T). Our structural studies provide the framework for understanding how RT\ndiscriminates between NRTIs and natural nucleotides, and for understanding the requirement of\n(-)FTC to undergo a conformation change for successful incorporation by RT. The crystal structure of\nRT in post-catalytic complex with d4T provides a â??snapshotâ? for considering the possible mechanism\nof how RT develops resistance for d4T via excision. The findings reported herein will contribute to\nthe development of next generation NRTIs
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