5e0i
Crystal structure of the HBV capsid Y132A mutant (VCID 8772) in complex with NVR10-001E2 at 1.95A resolution
Structural highlights
FunctionCAPSD_HBVD1 Self assembles to form an icosahedral capsid. Most capsid appear to be large particles with a icosahedral symmetry of T=4 and consist of 240 copies of capsid protein, though a fraction forms smaller T=3 particles consisting of 180 capsid proteins. Entering capsid are transported along microtubules to the nucleus. Phosphorylation of the capsid is thought to induce exposure of nuclear localization signal in the C-terminal portion of the capsid protein that allows binding to the nuclear pore complex via the importin (karyopherin-) alpha and beta. Capsids are imported in intact form through the nuclear pore into the nuclear basket, where it probably binds NUP153. Only capsids that contain the mature viral genome can release the viral DNA and capsid protein into the nucleoplasm. Immature capsids get stucked in the basket. Capsids encapsulate the pre-genomic RNA and the P protein. Pre-genomic RNA is reverse transcribed into DNA while the capsid is still in the cytoplasm. The capsid can then either be directed to the nucleus, providing more genome for transcription, or bud through the endoplasmic reticulum to provide new virions (By similarity).[1] Encapsidates hepatitis delta genome (By similarity).[2] Publication Abstract from PubMedThe hepatitis B virus (HBV) core protein is essential for HBV replication and an important target for antiviral drug discovery. We report the first, to our knowledge, high-resolution crystal structure of an antiviral compound bound to the HBV core protein. The compound NVR-010-001-E2 can induce assembly of the HBV core wild-type and Y132A mutant proteins and thermostabilize the proteins with a Tm increase of more than 10 degrees C. NVR-010-001-E2 binds at the dimer-dimer interface of the core proteins, forms a new interaction surface promoting protein-protein interaction, induces protein assembly, and increases stability. The impact of naturally occurring core protein mutations on antiviral activity correlates with NVR-010-001-E2 binding interactions determined by crystallography. The crystal structure provides understanding of a drug efficacy mechanism related to the induction and stabilization of protein-protein interactions and enables structure-guided design to improve antiviral potency and drug-like properties. High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein.,Klumpp K, Lam AM, Lukacs C, Vogel R, Ren S, Espiritu C, Baydo R, Atkins K, Abendroth J, Liao G, Efimov A, Hartman G, Flores OA Proc Natl Acad Sci U S A. 2015 Nov 23. pii: 201513803. PMID:26598693[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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