About

Hideki Aihara, PhD, is a professor affiliated with the Biochemistry, Molecular Biology & Biophysics department at the University of Minnesota. His laboratory utilizes structural biology techniques such as X-ray crystallography and cryo-electron microscopy to investigate important biological processes, particularly protein-DNA and protein-RNA interactions relevant to virology and cancer. His research topics include how retroviruses like HIV and HTLV integrate their genomes into host chromosomes, how the proofreading machinery of coronaviruses such as SARS-CoV-2 can be inhibited to prevent virus replication, and how human antiviral enzymes like APOBEC DNA cytosine deaminases introduce mutations in cancer genomes. Additionally, his work involves understanding and engineering DNA-modifying enzymes, including cytosine deaminases, for applications in genome editing.

Research topics

• Biology
• Genetics
• Medicine
• Virology
• Biochemistry
• Computational biology
• Chemistry
• Cell biology
• Internal medicine
• Biophysics
• Pharmacology
• Immunology

Selected publications

• Abstract 4423 Novel APOBEC3B-selective Nanobodies as Diagnostic and Therapeutic Tools

  Journal of Biological Chemistry · 2026-05-01

  articleOpen accessSenior author
  PublisherDOI

• Discovery, Structural Characterization, and Preclinical Evaluation of Monoclonal Antibodies against Xylazine Poisoning

  ACS Pharmacology & Translational Science · 2026-05-12

  article
  PublisherDOI

• Discovery and Characterization of Orthopoxvirus Resolvase Inhibitors with Antiviral Activity (Abstract ID: 275306)

  Journal of Pharmacology and Experimental Therapeutics · 2026-05-01

  article
  PublisherDOI

• The structural basis for the selective antagonism of soluble TNF-alpha by variable new antigen receptors

  Figshare · 2026-01-01

  datasetOpen access

  Data for the structures of VNARs D1 and C4 complexed to TNF-alpha

  PublisherDOI

• Structural basis for double-stranded DNA cytosine deamination by BaDTF3 and its application in mitochondrial genome editing

  Nature Communications · 2026-05-05

  articleOpen accessSenior authorCorresponding

  Bacterial deaminase toxin family (BaDTF) proteins are weapons used in bacterial warfare, and they are useful tools in base editing, epigenetics analyses, and genomic footprinting applications. Our previous studies revealed the mechanisms of 5’-TC-specific cytosine deamination in double-stranded (ds)DNA by DddA from BaDTF1 and sequence context-independent single-stranded (ss)DNA cytosine deamination by SsdA from BaDTF2. Here, we show that a representative member of BaDTF3, DddB, deaminates cytosines specifically in dsDNA, but with a broad sequence context preference. Our crystal structure of DddB bound to dsDNA reveals a distinct mechanism of substrate engagement, in which a helix-hairpin-helix motif inserted into the minor groove of dsDNA promotes flipping of the target cytosine into the enzyme active site. Based on the structural information, we generate both monomeric and split DddB-derived cytosine base editors (BdCBE) and demonstrate that they can perform CRISPR-free mitochondrial base editing in human cells, with an expanded targeting scope compared to the DddA-derived DdCBEs. Our studies highlight the mechanistic diversity among BaDTF proteins and expand the repertoire of dsDNA deaminase enzymes for genome editing and other applications. Bacterial DNA deaminase toxins are valuable tools in genome engineering. Here, authors reveal the mechanism of cytosine deamination in double-stranded DNA by BaDTF3/DddB, which is sequence context-nonselective and potentially useful for mitochondrial base editing.

  PublisherOA PDFDOI

• The structural basis for the selective antagonism of soluble TNF-alpha by variable new antigen receptors

  Figshare · 2026-01-01

  datasetOpen access

  Data for the structures of VNARs D1 and C4 complexed to TNF-alpha

  PublisherDOI

• Structural basis for bat receptor recognition by SARS-CoV-2 and bat SARS2-like coronaviruses

  Communications Biology · 2026-02-10

  articleOpen access

  Coronaviruses evolve to optimize receptor recognition in their natural hosts. A key mystery of COVID-19 is why the SARS-CoV-2 receptor-binding domain (RBD) binds human ACE2 with such high affinity despite limited time for adaptation, while some bat-derived RBDs paradoxically bind human ACE2 more strongly than bat ACE2. To investigate, we compared the RBDs of SARS-CoV-2 and BANAL-52, a related bat coronavirus, examining their interactions with ACE2 from Rhinolophus sinicus (RsBat) and from human. Structural and biochemical analyses revealed that BANAL-52 RBD is well adapted for binding to RsBat ACE2, with His498 of BANAL-52 RBD pairing favorably with His41 of RsBat ACE2. By contrast, SARS-CoV-2 RBD favors human ACE2, largely due to His34 and Met82 in human ACE2, residues that generally enhance RBD binding. These results show that receptor recognition by SARS-CoV-2 and related bat coronaviruses is consistent with established structural principles and provide structural insights relevant to the evolutionary origins of COVID-19. Structural and biochemical analyses resolve longstanding paradoxes in how SARS-CoV-2 and related bat viruses use their receptor-binding domains to recognize ACE2 receptors from human and bats, providing insights into the origins of COVID-19

  PublisherOA PDFDOI

• The atomic structure of human dystrophin spectrin-like repeat 24

  Acta Crystallographica Section F Structural Biology Communications · 2026-04-20

  articleOpen access

  The structure of spectrin-like repeat 24 of human dystrophin was determined at 2.5 Å effective resolution. The structure exhibits a three-helix bundle fold, common to all spectrin-repeat family members, and shares a high degree of homology with existing structures of spectrin-like repeat 1 from dystrophin and utrophin. The structure provides molecular details of the atomic interactions that stabilize the repeat, including hydrophobic interactions and inter-helix and intra-helix salt bridges. AlphaFold models of the repeat are in excellent agreement with the structure, showing an all-atom r.m.s.d. of 1.13 Å. Accurate modeling of SR24 supports AlphaFold modeling of all 24 of the dystrophin spectrin-like repeats and the use of these models in predicting the molecular determinants of dystrophin stability, a key aspect of its biological function as a structural protein that cross-links actin filaments to the dystrophin-glycoprotein complex to mediate a mechanical connection between the cytoskeleton and the extracellular matrix.

  PublisherDOI

• Direct interaction between human DDX1 and SARS-CoV-2 nucleocapsid protein is regulated by phosphorylation

  Journal of Biological Chemistry · 2026-03-26

  articleOpen access

  The nucleocapsid (N) protein of SARS-CoV-2 is essential for viral replication and transcription, in part through interactions with host proteins. Here, we delineate distinct mechanisms underlying N protein association with human RNA helicases DDX1 and DDX21. Co-immunoprecipitation assays in HEK293 cells modified to express N protein revealed that DDX1 binding requires the N protein serine-arginine (SR) region, as SR deletion markedly reduced interaction. Inhibition of glycogen synthase kinase-3 (GSK-3), which targets the SR region, serine-to-alanine substitutions within the SR region, and alkaline phosphatase treatment of extract, respectively, demonstrated that phosphorylation of the SR region is critical for DDX1 binding. Furthermore, phosphorylated or phospho-mimetic SR peptides both prevented N protein-DDX1 complex formation and disrupted preformed complexes in vitro, whereas unphosphorylated peptides had no effect, confirming a phosphorylation-dependent binding mechanism. In contrast, interaction with DDX21 was unaffected by SR deletion or phosphorylation status and required both the N- and C-terminal domains of the N protein. RNase treatment enhanced N-DDX21 association without altering N-DDX1 interactions, indicating distinct regulation by RNA. Domain mapping of the two helicases identified the DDX1 N-terminal and the DDX21 C-terminal domains as interfaces that bind the N protein. Together, these findings support phosphorylation-dependent recruitment of DDX1 versus phosphorylation-independent engagement of DDX21, highlighting mechanistically distinct strategies by which SARS-CoV-2 N co-opts host helicases.

  PublisherOA PDFDOI

• Development of Cell-Active BRD4-D1 Selective Inhibitors to Decode the Role of BET Proteins in LPS-Mediated Liver Inflammation

  SSRN Electronic Journal · 2025-01-01

  preprintOpen access
  PublisherDOI

Recent grants

• NIH Grant R33AI087098

  NIH · $1.1M · 2014

• PROJECT 3 – BIOLOGY OF DNA DEAMINASES IN CANCER

  NIH · $21.4M · 2019–2030

• Core D: Structural and Computational Virology

  NIH · $133.8M · 2022–2026

• NIH Grant R21AI087098

  NIH · $405k · 2011

• NIH Grant R01GM095558

  NIH · $1.4M · 2016

Frequent coauthors

• Ke Shi

  Beijing University of Technology

  139 shared

• Reuben S. Harris

  109 shared

• Michael A. Carpenter

  Public Health Agency of Canada

  56 shared

• Alex Dickson

  University of Strathclyde

  39 shared

• Daniel A. Harki

  University of Minnesota

  36 shared

• Paul C. Trippier

  University of Nebraska Medical Center

  36 shared

• Shiva Hadi Esfahani

  Oakland University

  36 shared

• Srinidhi Jayaraman

  Columbia University

  36 shared

Education

• Postdoctoral, Biochemistry and Molecular Biophysics

  Washington University School of Medicine in St. Louis

  2008

• Postdoctoral, Biological Chemistry and Molecular Pharmacology

  Harvard Medical School

  2006

• PhD, Biophysics and Biochemistry

  University of Tokyo

  2000

Awards & honors

• Dr. James E. Rubin Medical Memorial Award
• Graduating Medical Student Research Award
• Veneziale-Steer Award
• Dr. Marvin and Hadassah Bacaner Research Awards
• Schmidt Steer Award