Pei Zhou
Overview:
Protein-protein interactions play a pivotal role in the regulation of various cellular processes. The formation of higher order protein complexes is frequently accompanied by extensive structural remodeling of the individual components, varying from domain re-orientation to induced folding of unstructured elements. Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful tool for macromolecular structure determination in solution. It has the unique advantage of being capable of elucidating the dynamic behavior of proteins during the process of recognition. Recent advances in NMR techniques have enabled the study of significantly larger proteins and protein complexes. These innovations have also led to faster and more accurate structure determination. My research interests focus on the exploration of molecular recognition and conformation variability of protein complexes in crucial biomedical processes using state-of-the-art NMR techniques.
Positions:
Professor of Biochemistry
Biochemistry
School of Medicine
Professor of Chemistry
Chemistry
Trinity College of Arts & Sciences
Member of the Duke Cancer Institute
Duke Cancer Institute
School of Medicine
Education:
Ph.D. 1998
Harvard University
Post-Doct Fellow, Biological Chemistry
Harvard University
Grants:
Structural Biology and Biophysics Training Program
Administered By
Basic Science Departments
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date
Biochemical and functional investigation of the novel enzymatic activities of MESH1
Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date
Regulation of Germline Stem Cell Division in Drosophila
Administered By
Basic Science Departments
Awarded By
National Institutes of Health
Role
Consultant
Start Date
End Date
High sensitivity multi-purpose electron paramagnetic resonance spectroscopy for biotechnological and biomedical research
Administered By
Biochemistry
Awarded By
North Carolina Biotechnology Center
Role
Collaborating Investigator
Start Date
End Date
Discovery and validation of broadly effective LpxH inhibitors as novel therapeutics against multi-drug resistant Gram-negative pathogens
Administered By
Biochemistry
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date
Publications:
Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH.
Despite the widespread emergence of multidrug-resistant nosocomial Gram-negative bacterial infections and the major public health threat it brings, no new class of antibiotics for Gram-negative pathogens has been approved over the past five decades. Therefore, there is an urgent medical need for developing effective novel antibiotics against multidrug-resistant Gram-negative pathogens by targeting previously unexploited pathways in these bacteria. To fulfill this crucial need, we have been investigating a series of sulfonyl piperazine compounds targeting LpxH, a dimanganese-containing UDP-2,3-diacylglucosamine hydrolase in the lipid A biosynthetic pathway, as novel antibiotics against clinically important Gram-negative pathogens. Inspired by a detailed structural analysis of our previous LpxH inhibitors in complex with K. pneumoniae LpxH (KpLpxH), here we report the development and structural validation of the first-in-class sulfonyl piperazine LpxH inhibitors, JH-LPH-45 (8) and JH-LPH-50 (13), that achieve chelation of the active site dimanganese cluster of KpLpxH. The chelation of the dimanganese cluster significantly improves the potency of JH-LPH-45 (8) and JH-LPH-50 (13). We expect that further optimization of these proof-of-concept dimanganese-chelating LpxH inhibitors will ultimately lead to the development of more potent LpxH inhibitors for targeting multidrug-resistant Gram-negative pathogens.
MLA Citation
Kwak, Seung-Hwa, et al. “Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH.” Chemmedchem, Apr. 2023, p. e202300023. Pubmed, doi:10.1002/cmdc.202300023.
URI
https://scholars.duke.edu/individual/pub1572396
PMID
37014664
Source
pubmed
Published In
Chemmedchem
Published Date
Start Page
e202300023
DOI
10.1002/cmdc.202300023
Structure and dynamics of the Arabidopsis O-fucosyltransferase SPINDLY.
SPINDLY (SPY) in Arabidopsis thaliana is a novel nucleocytoplasmic protein O-fucosyltransferase (POFUT), which regulates diverse developmental processes. Sequence analysis indicates that SPY is distinct from ER-localized POFUTs and contains N-terminal tetratricopeptide repeats (TPRs) and a C-terminal catalytic domain resembling the O-linked-N-acetylglucosamine (GlcNAc) transferases (OGTs). However, the structural feature that determines the distinct enzymatic selectivity of SPY remains unknown. Here we report the cryo-electron microscopy (cryo-EM) structure of SPY and its complex with GDP-fucose, revealing distinct active-site features enabling GDP-fucose instead of UDP-GlcNAc binding. SPY forms an antiparallel dimer instead of the X-shaped dimer in human OGT, and its catalytic domain interconverts among multiple conformations. Analysis of mass spectrometry, co-IP, fucosylation activity, and cryo-EM data further demonstrates that the N-terminal disordered peptide in SPY contains trans auto-fucosylation sites and inhibits the POFUT activity, whereas TPRs 1-5 dynamically regulate SPY activity by interfering with protein substrate binding.
Authors
MLA Citation
Kumar, Shivesh, et al. “Structure and dynamics of the Arabidopsis O-fucosyltransferase SPINDLY.” Nat Commun, vol. 14, no. 1, Mar. 2023, p. 1538. Pubmed, doi:10.1038/s41467-023-37279-1.
URI
https://scholars.duke.edu/individual/pub1569373
PMID
36941311
Source
pubmed
Published In
Nature Communications
Volume
14
Published Date
Start Page
1538
DOI
10.1038/s41467-023-37279-1
Seeing is believing: Understanding functions of NPR1 and its paralogs in plant immunity through cellular and structural analyses.
In the past 30 years, our knowledge of how nonexpressor of pathogenesis-related genes 1 (NPR1) serves as a master regulator of salicylic acid (SA)-mediated immune responses in plants has been informed largely by molecular genetic studies. Despite extensive efforts, the biochemical functions of this protein in promoting plant survival against a wide range of pathogens and abiotic stresses are not completely understood. Recent breakthroughs in cellular and structural analyses of NPR1 and its paralogs have provided a molecular framework for reinterpreting decades of genetic observations and have revealed new functions of these proteins. Besides NPR1's well-known nuclear activity in inducing stress-responsive genes, it has also been shown to control stress protein homeostasis in the cytoplasm. Structurally, NPR4's direct binding to SA has been visualized at the molecular level. Analysis of the cryo-EM and crystal structures of NPR1 reveals a bird-shaped homodimer containing a unique zinc finger. Furthermore, the TGA32-NPR12-TGA32 complex has been imaged, uncovering a dimeric NPR1 bridging two TGA3 transcription factor dimers as part of an enhanceosome complex to induce defense gene expression. These new findings will shape future research directions for deciphering NPR functions in plant immunity.
Authors
Zhou, P; Zavaliev, R; Xiang, Y; Dong, X
MLA Citation
Zhou, Pei, et al. “Seeing is believing: Understanding functions of NPR1 and its paralogs in plant immunity through cellular and structural analyses.” Curr Opin Plant Biol, vol. 73, Mar. 2023, p. 102352. Pubmed, doi:10.1016/j.pbi.2023.102352.
URI
https://scholars.duke.edu/individual/pub1569176
PMID
36934653
Source
pubmed
Published In
Current Opinion in Plant Biology
Volume
73
Published Date
Start Page
102352
DOI
10.1016/j.pbi.2023.102352
Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy.
DNA damage tolerance and mutagenesis are hallmarks and enabling characteristics of neoplastic cells that drive tumorigenesis and allow cancer cells to resist therapy. The 'Y-family' trans-lesion synthesis (TLS) DNA polymerases enable cells to replicate damaged genomes, thereby conferring DNA damage tolerance. Moreover, Y-family DNA polymerases are inherently error-prone and cause mutations. Therefore, TLS DNA polymerases are potential mediators of important tumorigenic phenotypes. The skin cancer-propensity syndrome xeroderma pigmentosum-variant (XPV) results from defects in the Y-family DNA Polymerase Pol eta (Polη) and compensatory deployment of alternative inappropriate DNA polymerases. However, the extent to which dysregulated TLS contributes to the underlying etiology of other human cancers is unclear. Here we consider the broad impact of TLS polymerases on tumorigenesis and cancer therapy. We survey the ways in which TLS DNA polymerases are pathologically altered in cancer. We summarize evidence that TLS polymerases shape cancer genomes, and review studies implicating dysregulated TLS as a driver of carcinogenesis. Because many cancer treatment regimens comprise DNA-damaging agents, pharmacological inhibition of TLS is an attractive strategy for sensitizing tumors to genotoxic therapies. Therefore, we discuss the pharmacological tractability of the TLS pathway and summarize recent progress on development of TLS inhibitors for therapeutic purposes.
MLA Citation
Anand, Jay, et al. “Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy.” Nar Cancer, vol. 5, no. 1, Mar. 2023, p. zcad005. Pubmed, doi:10.1093/narcan/zcad005.
URI
https://scholars.duke.edu/individual/pub1565152
PMID
36755961
Source
pubmed
Published In
Nar Cancer
Volume
5
Published Date
Start Page
zcad005
DOI
10.1093/narcan/zcad005
From magic spot ppGpp to MESH1: Stringent response from bacteria to metazoa.
MLA Citation
Chi, Jen-Tsan, and Pei Zhou. “From magic spot ppGpp to MESH1: Stringent response from bacteria to metazoa.” Plos Pathog, vol. 19, no. 2, Feb. 2023, p. e1011105. Pubmed, doi:10.1371/journal.ppat.1011105.
URI
https://scholars.duke.edu/individual/pub1564868
PMID
36730138
Source
pubmed
Published In
Plos Pathog
Volume
19
Published Date
Start Page
e1011105
DOI
10.1371/journal.ppat.1011105

Professor of Biochemistry
Contact:
270 Sands Building, Research Drive, Durham, NC 27710
Duke Box 3711, Durham, NC 27710