2020 Research Highlights

Non-uniformity of projection distributions attenuates resolution in Cryo-EM

HIVE Center members explore ways to improve the quality of structures determined by cryoelectron microscopy.

Baldwin PR, Lyumkis D. Prog Biophys Mol Biol. 2020 150:160-183.

PubMed PMID: 31525386

PubMedCentral PMCID: PMC7054125

Structural and mechanistic bases for a potent HIV-1 capsid inhibitor

The structural basis of a potent inhibitor of capsid disassembly is revealed.

Bester SM, Wei G, Zhao H, Adu-Ampratwum D, Iqbal N, Courouble VV, Francis AC, Annamalai AS, Singh PK, Shkriabai N, Van Blerkom P, Morrison J, Poeschla EM, Engelman AN, Melikyan GB, Griffin PR, Fuchs JR, Asturias FJ, Kvaratskhelia M. Science. 2020 Oct 16;370(6514):360-364.

PubMed PMID: 33060363

PubMedCentral PMCID: PMC7831379

Selective and effective: Current progress in computational structure-based drug discovery of targeted covalent inhibitors

HIVE Center members review methods for the design of covalent inhibitors.

Bianco G, Goodsell DS, Forli S. Trends Pharmacol Sci. 2020 Dec;41(12):1038-1049.

PubMed PMID: 33153778

PubMedCentral PMCID: PMC7669701

Proline-rich domain of human ALIX contains multiple TSG101-UEV interaction sites and forms phosphorylation-mediated reversible amyloids

A proline-rich domain in ALIX forms amyloid fibrils and regulates the protein’s function.

Elias RD, Ma W, Ghirlando R, Schwieters CD, Reddy VS, Deshmukh L. Proc Natl Acad Sci U S A. 2020 Sep 29;117(39):24274-24284.

PubMed PMID: 32917811

PubMedCentral PMCID: PMC7533887

Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis

Interactions of HIV-1 integrase with RNA play several essential roles in the viral life cycle.

Elliott JL, Eschbach JE, Koneru PC, Li W, Puray-Chavez M, Townsend D, Lawson DQ, Engelman AN, Kvaratskhelia M, Kutluay SB. Elife. 2020 Sep 22;9:e54311. doi: 10.7554/eLife.54311.

PubMed PMID: 32960169

PubMedCentral PMCID: PMC7671690

Discovery of dihydroxyindole-2-carboxylic acid derivatives as dual allosteric HIV-1 Integrase and Reverse Transcriptase associated Ribonuclease H inhibitors

A new class of dual inhibitors is developed to block two HIV-1 enzymes.

Esposito F, Sechi M, Pala N, Sanna A, Koneru PC, Kvaratskhelia M, Naesens L, Corona A, Grandi N, di Santo R, D’Amore VM, Di Leva FS, Novellino E, Cosconati S, Tramontano E. Antiviral Res. 2020 174:104671.

PubMed PMID: 31812637

HIV-1 replication complexes accumulate in nuclear speckles and integrate into speckle-associated genomic domains

Nuclear entry and transport of HIV-1 replication complexes are imaged in cells.

Francis AC, Marin M, Singh PK, Achuthan V, Prellberg MJ, Palermino-Rowland K, Lan S, Tedbury PR, Sarafianos SG, Engelman AN, Melikyan GB. Nat Commun. 2020 Jul 14;11(1):3505.

PubMed PMID: 32665593

PubMedCentral PMCID: PMC7360574

Art and science of the cellular mesoscale

Techniques for modeling cellular and viral systems at molecular detail are reviewed.

Goodsell DS, Olson AJ, Forli S. Trends Biochem Sci. 2020 Jun;45(6):472-483.

PubMed PMID: 32413324

PubMedCentral PMCID: PMC7230070

Integrative illustration for coronavirus outreach

Illustrations of SARS structural biology have been widely used in education and outreach.

Goodsell DS, Voigt M, Zardecki C, Burley SK. PLoS Biol. 2020 Aug 6;18(8):e3000815. doi: 10.1371/journal.pbio.3000815.

PubMed PMID: 32760062

PubMedCentral PMCID: PMC7433897

Structural biology of HIV integrase strand transfer inhibitors

HIVE Center members review strand transfer inhibitors of HIV integrase.

Jóźwik IK, Passos DO, Lyumkis D. Trends Pharmacol Sci. 2020 Sep;41(9):611-626.

PubMed PMID: 32624197

PubMedCentral PMCID: PMC7429322

Sulfur(VI) fluoride exchange (SuFEx)-enabled high-throughput medicinal chemistry

A high-throughput hit-to-lead process allows discovery of covalent-binding inhibitors based on bioavailable SuFEx click chemistry.

Kitamura S, Zheng Q, Woehl JL, Solania A, Chen E, Dillon N, Hull MV, Kotaniguchi M, Cappiello JR, Kitamura S, Nizet V, Sharpless KB, Wolan DW. J Am Chem Soc. 2020 Jun 24;142(25):10899-10904.

PubMed PMID: 32479075

PubMedCentral PMCID: PMC7751259

Feasibility of known RNA polymerase inhibitors as anti-SARS-CoV-2 drugs

The nucleoside inhibitor binding pocket is largely conserved among diverse RNA-dependent RNA polymerases, but drug resistant mutations may be a problem.

Neogi U, Hill KJ, Ambikan AT, Heng X, Quinn TP, Byrareddy SN, Sönnerborg A, Sarafianos SG, Singh K.  Pathogens. 2020 Apr 26;9(5):320.

PubMed PMID: 32357471

PubMedCentral PMCID: PMC7281371

Binding interface and impact on protease cleavage for an RNA aptamer to HIV-1 reverse transcriptase

The interaction of a small, broad-spectrum RNA aptamer with HIV-1 reverse transcriptase is explored.

Nguyen PDM, Zheng J, Gremminger TJ, Qiu L, Zhang D, Tuske S, Lange MJ, Griffin PR, Arnold E, Chen SJ, Zou X, Heng X, Burke DH. Nucleic Acids Res. 2020 Mar 18;48(5):2709-2722.

PubMed PMID: 31943114

PubMedCentral PMCID: PMC7049723

A strain-specific inhibitor of receptor-bound HIV-1 targets a pocket near the fusion peptide

New compound targets the process of viral fusion.

Ozorowski G, Torres JL, Santos-Martins D, Forli S, Ward AB. Cell Rep. 2020 Nov 24;33(8):108428.

PubMed PMID: 33238117

PubMedCentral PMCID: PMC7701285

Structural basis for strand-transfer inhibitor binding to HIV intasomes

Cryo-electron microscopy is used to explore the structure of strand-transfer inhibitors of HIV-1 integrase.

Passos DO, Li M, Jóźwik IK, Zhao XZ, Santos-Martins D, Yang R, Smith SJ, Jeon Y, Forli S, Hughes SH, Burke TR Jr, Craigie R, Lyumkis D. Science. 2020 367(6479):810-814.

PubMed PMID: 32001521

PubMedCentral PMCID: PMC7357238

HIV-1 Gag protein with or without p6 specifically dimerizes on the viral RNA packaging signal

The role of p6 in the packaging of HIV genomic RNA is explored.

Sarni S, Biswas B, Liu S, Olson ED, Kitzrow JP, Rein A, Wysocki VH, Musier-Forsyth K. J Biol Chem. 2020 Oct 16;295(42):14391-14401.

PubMed PMID: 32817318

PubMedCentral PMCID: PMC7573273

Single-cell multiplexed fluorescence imaging to visualize viral nucleic acids and proteins and monitor HIV, HTLV, HBV, HCV, Zika virus, and influenza infection

New labeling approaches can follow viral DNA, RNA and protein inside infected cells.

Shah R, Lan S, Puray-Chavez MN, Liu D, Tedbury PR, Sarafianos SG. Single-cell J Vis Exp. 2020 Oct 29;(164):10.3791/61843.

PubMed PMID: 33191939

PubMedCentral PMCID: PMC7774762

Diversity Oriented Clicking (DOC): Divergent synthesis of SuFExable pharmacophores from 2-substituted-alkynyl-1-sulfonyl fluoride (SASF) hubs

Diversity Oriented Clicking streamlines the synthesis of libraries of covalent inhibitors.

Smedley CJ, Li G, Barrow AS, Gialelis TL, Giel MC, Ottonello A, Cheng Y, Kitamura S, Wolan DW, Sharpless KB, Moses JE. Angew Chem Int Ed Engl. 2020 Jul 20;59(30):12460-12469. doi: 10.1002/anie.202003219. Epub 2020 Jun 4.

PubMed PMID: 32301265

PubMedCentral PMCID: PMC7572632

HIV-1 integrase inhibitors that are active against drug-resistant integrase mutants

Some strand transfer inhibitors are effective for drug-resistant forms of integrase.

Smith SJ, Zhao XZ, Passos DO, Lyumkis D, Burke TR Jr, Hughes SH. Antimicrob Agents Chemother. 2020 Aug 20;64(9):e00611-20.

PubMed PMID: 32601157

PubMedCentral PMCID: PMC7449158

Exploring the free-energy landscape and thermodynamics of protein-protein association

Detailed energetics are explored as two subunits of HIV-1 integrase come together.

Tse C, Wickstrom L, Kvaratskhelia M, Gallicchio E, Levy R, Deng N. Biophys J. 2020 Sep 15;119(6):1226-1238.

PubMed PMID: 32877664

PubMedCentral PMCID: PMC7499063

Integrative structural biology studies of HIV-1 reverse transcriptase binding to a high-affinity DNA aptamer

HIVE Center researchers combine multiple experimental techniques to explore the binding of a DNA aptamer to reverse transcriptase.

Tuske S, Zheng J, Olson ED, Ruiz FX, Pascal BD, Hoang A, Bauman JD, Das K, DeStefano JJ, Musier-Forsyth K, Griffin PR, Arnold E.  Curr Res Struct Biol. 2020;2:116-129.

PubMed PMID: 33870216

PubMedCentral PMCID: PMC8052095

Evolving understanding of HIV-1 reverse transcriptase structure, function, inhibition, and resistance

The structural biology of HIV-1 reverse transcriptase is reviewed.

Xavier Ruiz F, Arnold E. Curr Opin Struct Biol. 2020 Apr;61:113-123.

PubMed PMID: 31935541

PubMedCentral PMCID: PMC7596924