CSSB Centre for Structural Systems Biology
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Hällberg Group

Structural Biochemistry of Herpesvirus Replication

Dr. Martin Hällberg

Group Leader

+49 40 8998 87578

Home Institute

Karolinska Institutet, Research Hotel

We focus on the structural-functional aspects of herpesvirus replication using an integrative structural biology approach.

Research Projects

Previous and Current Research

Existing therapies for herpesvirus infections are much less efficient than combination therapies against HIV. There is thus room for considerable improvement. We mean to address this issue by providing structural information about the hitherto most successful drug target: the viral machinery for synthesis of new virus DNA. We propose to use an integrative structural biology approach using a combination of biochemistry, x-ray crystallography, small-angle-xray scattering, single-particle cryo electron microscopy. Furthermore, in collaboration with the Grunewald group at the CSSB, the molecular knowledge will be combined with both ex-situ and in-situ cryo-electron tomography.

A better understanding of the molecular mechanisms of herpesvirus DNA replication will also result in a better understanding of the molecular mechanism responsible for development of the resistance to antiviral treatment. We expect that such insights will also contribute to our understanding of the treatment of neoplastic disease and open up novel avenues for therapeutic intervention also in this arena.

Since herpesviruses always establish latency in infected individuals, their prevalence increases with age and may approach 100% in higher age groups for several herpesviruses. In modern medicine, where immune suppression is used during transplantation, the reactivation of a latent virus is a serious and potentially life-threatening complication. These are also conditions during which the development of resistance towards antiviral compounds increases more than ten-fold and may reach 10–20%.

Herpesvirus replication

All herpesviruses share the same strategy for DNA replication. The mechanisms and the enzymes involved differ from the cellular counterparts, and they are therefore attractive as antiviral targets. Herpesviruses make use of a molecular machine, a replisome, consisting of six interacting proteins to synthesise double-stranded DNA. The replisome is assembled at origins of replication.

 Herpesviruses replicate their DNA in two phases during a productive infectious cycle. First, circular molecules are amplified by an origin-dependent bidirectional replication. In a second phase, the circular molecules are used by a rolling circle mode of replication generating linear concatemers, which are cleaved into unit length molecules and packaged into capsids. For herpes simplex virus, DNA replication occurs simultaneously with frequent recombination and processing of replication intermediates 

At present, there is limited insight into the structural biology of Herpes simplex virus replication. So far X-ray crystallography has provided structures for the UL30 DNA polymerase subunit, UL42 in complex with a C-terminal peptide from UL30 and ICP8 lacking the C-terminal 60 amino acids required for formation of filaments. Clearly, more work is needed to provide insights into the structure of the complete replisome, individual components of the herpes replisome and complexes of replication proteins in discrete functional states.


Future projects and goals

We aim to determine the structural-functional basis of herpesvirus replication using a combination of techniques available in the CSSB. Our molecular results will be integrated with results on herpesvirus replication in-situ from the Grunewald group at the CSSB thereby studying the mechanism of herpesvirus from several angles and scales in an integrative structural biology approach.

Research Team


Group Leader

Dr. Martin Hällberg
Phone:+49 40 8998 87578


Postdoctoral Scientist

Emil Gustavsson
Phone:+49 040 8998 87717




Hanke L, Das H, Sheward DJ, Perez Vidakovics L, Urgard E, Moliner-Morro A, Kim C, Karl V, Pankow A, Smith NL, Porebski B, Fernandez-Capetillo O, Sezgin E, Pedersen GK, Coquet JM, Hällberg BM, Murrell B, McInerney GM (2021) A bispecific monomeric nanobody induces spike trimer dimers and neutralizes SARS-CoV-2 in vivo. bioRxiv 2021.03.20.436243; doi: https://doi.org/10.1101/2021.03.20.436243

Valentín Gesé G, Shahzad S, Pardo-Hernández C, Wramstedt A, Falkenberg M, Hällberg BM (2021) A dual allosteric pathway drives human mitochondrial Lon. bioRxiv 2021.06.09.447696; doi: https://doi.org/10.1101/2021.06.09.447696

Cipullo M, Gesé GV, Khawaja A, Hällberg BM, Rorbach J (2021) Structural basis for late maturation steps of the human mitoribosomal large subunit. Nat Commun. 12(1):3673. doi: 10.1038/s41467-021-23617-8.

Koenig PA, Das H, Liu H, Kümmerer BM, Gohr FN, Jenster LM, Schiffelers LDJ, Tesfamariam YM, Uchima M, Wuerth JD, Gatterdam K, Ruetalo N, Christensen MH, Fandrey CI, Normann S, Tödtmann JMP, Pritzl S, Hanke L, Boos J, Yuan M, Zhu X, Schmid-Burgk JL, Kato H, Schindler M, Wilson IA, Geyer M, Ludwig KU, Hällberg BM, Wu NC, Schmidt FI (2021) Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape. Science.371(6530):eabe6230 doi: 10.1126/science.abe6230.


Custódio TF, Das H, Sheward DJ, Hanke L, Pazicky S, Pieprzyk J, Sorgenfrei M, Schroer M, Gruzinov A, Jeffries C, Graewert M, Svergun D, Dobrev N, Remans K, Seeger MA, McInerney GM, Murrell B, Hällberg MB, Löw C (2020) Selection, biophysical and structural analysis of synthetic nanobodies that effectively neutralize SARS-CoV-2. Nat Commun.11(1):4420. doi: 10.1038/s41467-020-19204-y.

Wu PS, Enervald E, Joelsson A, Palmberg C, Rutishauser D, Hällberg BM, Ström L. Genetics (2020) Posttranslational Regulation of DNA Polymerase η, a Connection to Damage-Induced Cohesion in Saccharomyces cerevisiae. genetics.303494.2020. doi: 10.1534/genetics.120.303494.

Hanke L, Vidakovics Perez L, Sheward DJ, Das H, Schulte T, Moliner-Morro A, Corcoran M, Achour A, Karlsson Hedestam GB, Hällberg BM, Murrell B, McInerney GM (2020) An alpaca nanobody neutralizes SARS-CoV-2 by blocking receptor interaction. Nat Commun.11(1):4420. doi: 10.1038/s41467-020-18174-5.


Reinhard L, Sridhara S, Hällberg BM. (2017) The MRPP1/MRPP2 complex is a tRNA-maturation platform in human mitochondria. Nucleic Acids Res 45:12469-12480. doi: 10.1093/nar/gkx902

Walldén K, Nyman T, Hällberg BM (2017) SnoN Stabilizes the SMAD3/SMAD4 Protein Complex. Sci Rep 7, 46370. doi: 10.1038/srep46370.


Lapkouski M, Hällberg BM (2015)  Structure of mitochondrial poly(A) RNA polymerase reveals the structural basis for dimerization, ATP selectivity and the SPAX4 disease phenotype. Nucleic Acids Res 43:9065-9075.  doi: 10.1093/nar/gkv861.

Tan TC, Kracher D, Gandini R, Sygmund C, Kittl R, Haltrich D, Hällberg BM, Ludwig R, Divne C (2015) Structural basis for cellobiose dehydrogenase action during oxidative cellulose degradation. Nature communications 6:7542.  doi: 10.1038/ncomms8542.

Reinhard L, Sridhara S, Hällberg BM (2015) Structure of the nuclease subunit of human mitochondrial RNase P. Nucleic Acids Res 43:5664-5672.  doi: 10.1093/nar/gkv481

Posse V, Shahzad S, Falkenberg M, Hällberg BM, Gustafsson CM (2015)  TEFM is a potent stimulator of mitochondrial transcription elongation in vitro. Nucleic Acids Res 43:2615-2624. doi: 10.1093/nar/gkv105.


Hällberg BM, Larsson NG (2014) Making proteins in the powerhouse. Cell Metabolism 20:226-240. doi: 10.1016/j.cmet.2014.07.001.

Posse V, Hoberg E, Dierckx A, Shahzad S, Koolmeister C, Larsson NG, Wilhelmsson, LM, Hallberg, BM, Gustafsson CM (2014) The amino terminal extension of mammalian mitochondrial RNA polymerase ensures promoter specific transcription initiation  Nucleic Acids Res 42:3638-3647. doi: 10.1093/nar/gkt1397


Spåhr H, Habermann B, Gustafsson CM, Larsson NG, Hällberg BM (2012) Structure of the MTERF4-NSUN4 complex that regulates mitochondrial ribosome biogenesis. PNAS 109, 15253-15258. doi: 10.1073/pnas.1210688109


Cámara Y, Asin-Cayuela J, Park CB, Metodiev MD, Shi Y, Ruzzenente B, Kukat C, Habermann B, Wibom R, Hultenby K, Franz T, Erdjument-Bromage H, Tempst P, Hällberg BM, Gustafsson CM, Larsson NG (2011) MTERF4 regulates translation by targeting the methyltransferase NSUN4 to the mammalian mitochondrial ribosome. Cell Metabolism. 13, 527-539.

Busam RD, Thorsell AG, Flores A, Hammarström M, Persson C, Öbrink B, Hällberg BM (2011) Structural basis of tumor suppressor in lung cancer 1 (TSLC1) binding to differentially expressed in adenocarcinoma of the lung (DAL-1/4.1B). J. Biol. Chem. 286, 4511-4516. Highlighted in Nature Structural and Molecular Biology 18, 5.

Hällberg BM, Larsson NG (2011) TFAM forces mtDNA to make a U-turn. Nature Struct Mol Biol. 18, 1179-1181.


Spåhr H, Samuelsson T, Hällberg BM, Gustafsson CM (2010) Structure of mitochondrial transcription termination factor 3 reveals a novel nucleic acid-binding domain. Biochem Biophys Res Commun. 397, 386-90.


Thorsell AG, Persson C, Gräslund S, Hammarström M, Busam RD, Hällberg BM (2009) Crystal structure of human diphosphoinositol phosphatase 1. Proteins. 77, 242-246.

Seif E, Hällberg BM (2009) RNA-protein mutually induced Fit: Structure of E. coli isopentenyl-tRNA transferase in complex with tRNA(Phe). J. Biol. Chem. 284, 6600-6604.


Thorsell AG, Persson C, Voevedskaya N, Busam RD,  Hammarstrom M, Gräslund S, Gräslund A, Hällberg BM (2008) Structural and biophysical characterisation of human myo-inositol oxygenase. J. Biol. Chem. 283, 15209-15216.

Gräslund S, Nordlund P, Weigelt J, Hallberg BM, Bray J, Gileadi O, Knapp S, Oppermann U, Arrowsmith C, Hui R, Ming J, dhe-Paganon S, Park HW, Savchenko A, Yee A, Edwards A#, Vincentelli R, Cambillau C, Kim R, Kim SH, Rao Z, Shi Y, Terwilliger TC, Kim CY, Hung LW, Waldo GS, Peleg Y, Albeck S, Unger T, Dym O, Prilusky J, Sussman JL, Stevens RC, Lesley SA, Wilson IA, Joachimiak A, Collart F, Dementieva I, Donnelly MI, Eschenfeldt WH, Kim Y, Stols L, Wu R, Zhou M, Burley SK, Emtage JS, Sauder JM, Thompson D, Bain K, Luz J, Gheyi T, Zhang F, Atwell S, Almo SC, Bonanno JB, Fiser A, Swaminathan S, Studier FW, Chance MR, Sali A, Acton TB, Xiao R, Zhao L, Ma LC, Hunt JF, Tong L, Cunningham K, Inouye M, Anderson S, Janjua H, Shastry R, Ho CK, Wang D, Wang H, Jiang M, Montelione GT, Stuart DI, Owens RJ, Daenke S, Schütz A, Heinemann U, Yokoyama S, Büssow K, Gunsalus KC (2008) Protein production and purification. Nature Methods 5, 135-146.


Vilhelmsson M, Selander C, Zargari A, Rasool O, Achour A, Scheynius A, Hällberg BM (2007) Crystal structure of the major Malassezia sympodialis allergen reveals a β-propeller fold: A novel fold among allergens. J. Mol. Biol 369, 1079-1086.


Bakali MA, Herman MD, Johnson KA, Kelly A, Wieslander Å, Hällberg BM, Nordlund P (2006) Crystal structure of YegS, a homologue to mammalian diacylglycerol kinases, reveals a novel regulatory metal binding site. J. Biol. Chem. 282, 19644-19652.

Busam RD, Thorsell AG, Flores A, Hammarstrom M, Persson C, Hällberg BM First structure of a eukaryotic phosphohistidine phosphatase. (2006) J. Biol. Chem. 281, 33830-33834.

Kujawa M, Ebner H, Leitner C, Hällberg BM, Prongjit M, Sucharitakul J, Ludwig R, Rudsander U, Peterbauer C, Chaiyen P, Haltrich D, Divne C. (2006) Structural basis for substrate binding and regioselective oxidation of monosaccharides at C3 by pyranose 2-oxidase. J. Biol. Chem. 281 35104-35115.

Hällberg BM, Ericsson UB, Johnson KA, Møller Andersen N, Douthwaite S, Nordlund P, Erlandsen H (2006) The structure of YebU, an RNA m5C methyltransferase from E.coli reveals a C-terminal RNA-recruiting PUA domain. J. Mol. Biol. 360, 774-787.

Ericsson UB, Hällberg BM, DeTitta GT, Dekker N, Nordlund P (2006) Thermofluor based high-throughput stability optimisation of proteins for structural and functional studies. Analytical Biochemistry 357, 289-298.

Johnson KA, Stahl A, Bhushan S, Hällberg BM, Glaser E, Eneqvist T (2006) The closed structure of presequence protease PreP forms a unique 10 000 A(3) chamber for proteolysis. EMBO J., 25, 1977-1986.

Bakali MA, Nordlund P, Hällberg BM (2006) Expression, purification, crystallization and preliminary diffraction studies of the mammalian DAG kinase homologue YegS from Escherichia coli. Acta Cryst. F, 62, 295-297.

Zamocky M, Ludwig R, Peterbauer C, Hällberg BM, Divne C, Nicholls P, Haltrich D (2006) Cellobiose dehydrogenase - a flavocytochrome from wood-degrading, phytopathogenic, and saprothrophic fungi. Current Protein and Peptide Science. 7, 255-280.

Vilhelmsson MS, Hällberg BM, Rasool O, Zargari A, Scheynius A, Achour A (2006) Crystallization and preliminary crystallographic study of the yeast Malassezia sympodialis allergen Mala s 1. Acta Cryst. F, 62, 97-99. Shared contribution.


Hopfmann KH, Hällberg BM, Hihmo F (2005) Catalytic mechanism of Limonene Epoxide hydrolase, a theoretical study. JACS 127, 14339-14447.


Hällberg BM, Leitner C, Haltrich D, Divne C (2004) Crystal Structure of the 270 kDa homotetrameric lignin degrading enzyme pyranose 2-oxidase J. Mol. Biol. 341, 781-796.

Zamocky M, Hällberg M, Ludwig R, Divne C, Haltrich D (2004) Ancestral gene fusion in cellobiose dehydrogenase reflects a specific evolution of GMC oxidoreductases in fungi. Gene 338, 1-14.

Eriksson UB, Nordlund P, Hällberg BM (2004) X-ray structure of tRNA pseudouridine synthase TruD reveals an inserted domain with a novel fold. FEBS Lett. ,565, 59-64.

Ericsson UB, Andersson ME, Engvall B, Nordlund P, Hällberg BM (2004) Expression, purification, crystallization and preliminary diffraction studies of the tRNA pseudouridine synthase TruD from Escherichia  coli. Acta Crystallogr D. 60, 775-776.

Hällberg BM, Leitner C, Haltrich D, Divne C (2004) Crystallization and preliminary X-ray diffraction analysis of pyranose 2-oxidase from the white-rot fungus Trametes multicolor. Acta Crystallogr D. 60, 197-199.


Rotsaert FAS, Hällberg BMS, de Vries S, Moenne-Loccoz P, Divne C, Renganathan V, Gold MH (2003) Biophysical and structural analysis of a novel heme B iron ligation in the flavocytochrome cellobiose dehydrogenase. J. Biol. Chem. 278, 33224-33231. S Shared contribution.

Arand M, Hällberg BM, Zou J, Bergfors T, Oesch F, van der Werf MJ, de Bont JA, Jones TA, Mowbray SL (2003) Structure of Rhodococcus erythropolis limonene-1,2-epoxide hydrolase reveals a novel active site. EMBO J. 22, 2583-2592.

Campanacci V, Lartigue A, Hällberg BM, Jones TA, Giudici-Orticoni MT, Tegoni M, Cambillau C (2003) Moth chemosensory protein exhibits drastic conformational changes and cooperativity on ligand binding. PNAS  100, 5069-5074.

Mason MG, Nicholls P, Divne C, Hällberg BM, Henriksson G, Wilson MT (2003)  The heme domain of cellobiose oxidoreductase: a one-electron reducing system. Biochim. Biophys. Acta 1604, 47-54.

Hällberg BM, Henriksson G, Pettersson G, Vasella A, Divne C (2003) Mechanism of the reductive half-reaction in cellobiose dehydrogenase. J. Biol. Chem. 278, 7160-7166.


Hällberg BM, Henriksson G, Pettersson G, Divne C (2002) Crystal structure of the flavoprotein domain of the extracellular flavocytochrome cellobiose dehydrogenase. J. Mol. Biol. 315, 421-434.

Raices M, Montesino R, Cremata J, Garcia B, Perdomo W, Szabo I, Henriksson G, Hällberg BM, Pettersson G,  Johansson G (2002) Cellobiose quinone oxidoreductase from the white rot fungus Phanerochaete chrysosporium is produced by intracellular proteolysis of cellobiose dehydrogenase. Biochim. Biophys. Acta 1576, 15-22.

Yoshida M, Ohira T, Igarashi K, Nagasawa H, Aida K, Hällberg BM, Divne C, Nishino T, Samejima M (2001) Production and characterization of recombinant Phanerochaete  chrysosporium cellobiose dehydrogenase in the methylotrophic yeast Pichia pastoris. Biosci. Biotechnol. Biochem. 65, 2050-2057.


Zou J, Hällberg BM, Bergfors T, Oesch F, Arand M, Mowbray SL, Jones TA (2000) Structure of Aspergillus niger epoxide hydrolase at 1.8 Å resolution: implications for the structure and function of the mammalian microsomal class of epoxide hydrolases. Structure 8, 111-122.

Hällberg BM, Bergfors T, Bäckbro K, Pettersson G, Henriksson G, Divne C (2000) A new scaffold for binding of haem in the cytochrome domain of the extracellular flavocytochrome cellobiose dehydrogenase. Structure 8, 79-88.