About

Philip J. Kranzusch, Ph.D., is a Professor of Microbiology affiliated with the Department of Cancer Immunology & Virology at the Dana-Farber Cancer Institute and the Department of Microbiology at Harvard Medical School. His laboratory, the Kranzusch Lab, focuses on research at the intersection of biochemistry and immunology. The lab actively seeks researchers with a strong interest in these fields, including graduate students and postdoctoral fellows with backgrounds in biochemistry, immunology, or virology. Prospective members are encouraged to apply to graduate programs at Harvard Medical School or contact the lab directly for rotation opportunities or postdoctoral positions. The lab maintains a collaborative environment with a diverse team of graduate students, postdoctoral fellows, and research technicians working on various projects related to the lab's research focus.

Research topics

• Biology
• Cell biology
• Genetics
• Biochemistry
• Microbiology
• Virology
• Computational biology
• Immunology

Selected publications

• Nuclease–NTPase antiphage defence systems use conserved molecular features to control bacterial immunity

  Nature Microbiology · 2026-04-27 · 1 citations

  articleSenior author
  PublisherDOI

• Mechanisms of HSV-1 helicase-primase inhibition and replication fork complex assembly

  Cell · 2025-12-29 · 1 citations

  articleOpen access

  Herpesviruses are widespread double-stranded DNA viruses that establish lifelong latency and cause various diseases. Although DNA-polymerase-targeting antivirals are effective, increasing drug resistance underscores the need for alternatives. Helicase-primase inhibitors (HPIs) are promising antivirals, but their mechanisms of action are poorly defined. Furthermore, how the helicase-primase (H/P) complex and DNA polymerase coordinate genome replication is not well understood for herpesviruses. Here, we report cryo-electron microscopy (cryo-EM) structures of the herpes simplex virus 1 H/P complex bound to HPIs, showing that these lock the H/P complex in an inactive state. Single-molecule assays reveal that HPIs cause H/P complexes to pause in unwinding activity on DNA. The structure of an HPI-bound replication fork complex, comprising the H/P complex (UL5, UL52, and UL8) and the polymerase holoenzyme (UL30 and UL42), reveals a previously uncharacterized interface bridging these complexes. These findings provide a structural framework for understanding herpesvirus replisome assembly and advancing inhibitor development.

  PublisherDOI

• A widespread family of viral sponge proteins reveals specific inhibition of nucleotide signals in anti-phage defense

  Molecular Cell · 2025-08-01 · 9 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• CARD domains mediate anti-phage defence in bacterial gasdermin systems

  Nature · 2025-01-29 · 24 citations

  articleOpen access
  PublisherOA PDFDOI

• Structural basis of QueC-family protein function in qatABCD anti-phage defense

  Nature Communications · 2025-09-03 · 3 citations

  preprintOpen accessSenior authorCorresponding

  QueC proteins are nucleoside biosynthesis enzymes required for production of the 7-deazaguanine derivative queuosine. Recently, QueC-family proteins were also shown to catalyze a deazaguanylation protein-nucleobase conjugation reaction in type IV CBASS bacterial anti-phage defense. Here we determine the structural basis of QueC-family protein function in a distinct bacterial immunity system named qatABCD. We demonstrate that the Pseudomonas aeruginosa QueC-family protein QatC forms a specific complex with the immunity protein QatB and that this complex is minimally required for qatABCD defense. Crystal structures of the QatBC complex enable direct comparison of qatABCD and type IV CBASS defense and support a shared role for QueC-family proteins in targeting protein substrates for N-terminal modification. We show that the QatB unstructured N-terminus and N-terminal glycine motif are essential for qatABCD defense in vivo, suggesting a modification occurs analogous to CBASS deazaguanylation. These findings highlight broad roles of QueC proteins beyond nucleoside biosynthesis and suggest that adaptation of QueC-like proteins for specialized biochemical functions is a common strategy in bacterial anti-phage immunity.

  PublisherDOI

• Structural modeling reveals viral proteins that manipulate host immune signaling

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-12 · 4 citations

  preprintOpen access

  Immune pathways that use intracellular nucleotide signaling are common in animals, plants and bacteria. Viruses can inhibit nucleotide immune signaling by producing proteins that sequester or cleave the immune signals. Here we analyzed evolutionarily unrelated signal-sequestering viral proteins, finding that they share structural and biophysical traits in their genetic organization, ternary structures and binding pocket properties. Based on these traits we developed a structure-guided computational pipeline that can sift through large phage genome databases to unbiasedly predict phage proteins that manipulate bacterial immune signaling. Numerous previously uncharacterized proteins, grouped into three families, were verified to inhibit the bacterial Thoeris and CBASS signaling systems. Proteins of the Sequestin and Lockin families bind and sequester the TIR-produced signaling molecules 3'cADPR and His-ADPR, while proteins of the Acb5 family cleave and inactivate 3'3'-cGAMP and related molecules. X-ray crystallography and structural modeling, combined with mutational analyses, explain the structural basis for sequestration or cleavage of the immune signals. Thousands of these signal-manipulating proteins were detected in phage protein databases, with some instances present in well-studied model phages such as T2, T4 and T6. Our study explains how phages commonly evade bacterial immune signaling, and offers a structure-guided analytical approach for discovery of viral immune-manipulating proteins in any database of choice.

  PublisherOA PDFDOI

• Activating and inhibiting nucleotide signals coordinate bacterial anti-phage defense

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-09 · 1 citations

  preprintOpen accessSenior authorCorresponding

  The cellular nucleotide pool is a major focal point of the host immune response to viral infection. Immune effector proteins that disrupt the nucleotide pool allow animal and bacterial cells to broadly restrict diverse viruses, but reduced nucleotide availability induces cellular toxicity and can limit host fitness(Ahmad et al., 1998; Goldstone et al., 2011; Hsueh et al., 2022; Itsko & Schaaper, 2014; Tal et al., 2022). Here we discover a bacterial anti-phage defense system named Clover that overcomes this tradeoff by encoding a deoxynucleoside triphosphohydrolase enzyme (CloA) that dynamically responds to both an activating phage cue and an inhibitory nucleotide immune signal produced by a partnering regulatory enzyme (CloB). Analysis of Clover phage restriction in cells and reconstitution of enzymatic function in vitro demonstrate that CloA is a dGTPase that responds to viral enzymes that increase cellular levels of dTTP. To restrain CloA activation in the absence of infection, we show that CloB synthesizes a dTTP-related inhibitory nucleotide signal p3diT (5'-triphosphothymidyl-3'5'-thymidine) that binds to CloA and suppresses activation. Cryo-EM structures of CloA in activated and suppressed states reveal how dTTP and p3diT control distinct allosteric sites and regulate effector function. Our results define how nucleotide signals coordinate both activation and inhibition of antiviral immunity and explain how cells balance defense and immune-mediated toxicity.

  PublisherOA PDFDOI

• Deazaguanylation is a nucleobase-protein conjugation required for type IV CBASS immunity

  Science · 2025-09-25 · 3 citations

  articleOpen accessSenior authorCorresponding

  7-Deazapurines are nucleobase analogs essential for nucleic acid modifications in nearly all cellular life. In this study, we discovered a role for 7-deazapurines in protein modification within type IV cyclic oligonucleotide-based antiviral signaling system (CBASS) antiphage defense and defined functions for CBASS ancillary proteins Cap9 and Cap10 in nucleobase-protein conjugation. A structure of Cap10 revealed a transfer RNA transglycosylase family enzyme remodeled to bind a partner cGAS/DncV-like nucleotidyltransferase that is modified with an N-terminal 7-amido-7-deazaguanine (NDG) nucleobase. A structure of Cap9 explained how this QueC-like enzyme co-opts a 7-deazapurine biosynthetic reaction to install NDG. We show that Cap9, Cap10, and protein deazaguanylation are essential for host defense against phage infection. Our results define a 7-deazapurine protein modification and explain how nucleobase biosynthetic machinery has been repurposed for antiviral immunity.

  PublisherOA PDFDOI

• TIR domains produce histidine-ADPR as an immune signal in bacteria

  Nature · 2025-04-30 · 34 citations

  article
  PublisherDOI

• Structure of Acb2 homolog 43 in complex with 3'cADPR

  2025-07-29

  datasetSenior author
  PublisherDOI

Frequent coauthors

• B. Lowey

  Yale University

  70 shared

• Alex G. Johnson

  58 shared

• Wen Zhou

  Southern University of Science and Technology

  45 shared

• Rotem Sorek

  Weizmann Institute of Science

  40 shared

• Apurva A. Govande

  Dana-Farber Cancer Institute

  39 shared

• Gil Amitai

  Weizmann Institute of Science

  35 shared

• B.R. Morehouse

  University of California, Irvine

  34 shared

• Allen Lu

  Harvard University

  31 shared

Labs

• Kranzusch LabPI

  Research on host-virus interactions, biochemical and structural approaches to study viral infection and innate immunity, and the mechanisms viruses use to avoid antiviral defense.