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
Cell Biology
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
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:

Metabolic engineering of Escherichia coli to produce a monophosphoryl lipid A adjuvant.

Monophosphoryl lipid A (MPLA) species, including MPL (a trade name of GlaxoSmithKline) and GLA (a trade name of Immune Design, a subsidiary of Merck), are widely used as an adjuvant in vaccines, allergy drugs, and immunotherapy to boost the immune response. Even though MPLA is a derivative of lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, bacterial strains producing MPLA have not been found in nature nor engineered. In fact, MPLA generation involves expensive and laborious procedures based on synthetic routes or chemical transformation of precursors isolated from Gram-negative bacteria. Here, we report the engineering of an Escherichia coli strain for in situ production and accumulation of MPLA. Furthermore, we establish a succinct method for purifying MPLA from the engineered E. coli strain. We show that the purified MPLA (named EcML) stimulates the mouse immune system to generate antigen-specific IgG antibodies similarly to commercially available MPLA, but with a dramatically reduced manufacturing time and cost. Our system, employing the first engineered E. coli strain that directly produces the adjuvant EcML, could transform the current standard of industrial MPLA production.
Authors
Ji, Y; An, J; Hwang, D; Ha, DH; Lim, SM; Lee, C; Zhao, J; Song, HK; Yang, EG; Zhou, P; Chung, HS
MLA Citation
Ji, Yuhyun, et al. “Metabolic engineering of Escherichia coli to produce a monophosphoryl lipid A adjuvant..” Metab Eng, vol. 57, Nov. 2019, pp. 193–202. Pubmed, doi:10.1016/j.ymben.2019.11.009.
URI
https://scholars.duke.edu/individual/pub1423417
PMID
31786244
Source
pubmed
Published In
Metab Eng
Volume
57
Published Date
Start Page
193
End Page
202
DOI
10.1016/j.ymben.2019.11.009

The lipid A 1-phosphatase, LpxE, play multiple roles in bacteria envelope biogenesis

Authors
An, J; Zhao, J; Hwang, D; Gillespie, RA; Yang, EG; Zhou, P; Chung, HS
MLA Citation
An, Jinsu, et al. “The lipid A 1-phosphatase, LpxE, play multiple roles in bacteria envelope biogenesis.” Faseb Journal, vol. 32, no. 1, FEDERATION AMER SOC EXP BIOL, 2018.
URI
https://scholars.duke.edu/individual/pub1383996
Source
wos
Published In
Faseb Journal
Volume
32
Published Date

Synthesis and biological evaluation of sulfonyl piperazine derivatives for LpxH inhibition

Authors
Lee, M; Zhao, J; Cho, J; Kwon, D-Y; Zhou, P; Hong, J
MLA Citation
Lee, Minhee, et al. “Synthesis and biological evaluation of sulfonyl piperazine derivatives for LpxH inhibition.” Abstracts of Papers of the American Chemical Society, vol. 253, AMER CHEMICAL SOC, 2017.
URI
https://scholars.duke.edu/individual/pub1316030
Source
wos
Published In
Abstracts of Papers of the American Chemical Society
Volume
253
Published Date

Drug design from the cryptic inhibitor envelope.

Conformational dynamics plays an important role in enzyme catalysis, allosteric regulation of protein functions and assembly of macromolecular complexes. Despite these well-established roles, such information has yet to be exploited for drug design. Here we show by nuclear magnetic resonance spectroscopy that inhibitors of LpxC--an essential enzyme of the lipid A biosynthetic pathway in Gram-negative bacteria and a validated novel antibiotic target--access alternative, minor population states in solution in addition to the ligand conformation observed in crystal structures. These conformations collectively delineate an inhibitor envelope that is invisible to crystallography, but is dynamically accessible by small molecules in solution. Drug design exploiting such a hidden inhibitor envelope has led to the development of potent antibiotics with inhibition constants in the single-digit picomolar range. The principle of the cryptic inhibitor envelope approach may be broadly applicable to other lead optimization campaigns to yield improved therapeutics.
Authors
Lee, C-J; Liang, X; Wu, Q; Najeeb, J; Zhao, J; Gopalaswamy, R; Titecat, M; Sebbane, F; Lemaitre, N; Toone, EJ; Zhou, P
MLA Citation
Lee, Chul-Jin, et al. “Drug design from the cryptic inhibitor envelope..” Nat Commun, vol. 7, Feb. 2016. Pubmed, doi:10.1038/ncomms10638.
URI
https://scholars.duke.edu/individual/pub1121771
PMID
26912110
Source
pubmed
Published In
Nature Communications
Volume
7
Published Date
Start Page
10638
DOI
10.1038/ncomms10638

Structural basis of the promiscuous inhibitor susceptibility of Escherichia coli LpxC.

The LpxC enzyme in the lipid A biosynthetic pathway is one of the most promising and clinically unexploited antibiotic targets for treatment of multidrug-resistant Gram-negative infections. Progress in medicinal chemistry has led to the discovery of potent LpxC inhibitors with a variety of chemical scaffolds and distinct antibiotic profiles. The vast majority of these compounds, including the nanomolar inhibitors L-161,240 and BB-78485, are highly effective in suppressing the activity of Escherichia coli LpxC (EcLpxC) but not divergent orthologs such as Pseudomonas aeruginosa LpxC (PaLpxC) in vitro. The molecular basis for such promiscuous inhibition of EcLpxC has remained poorly understood. Here, we report the crystal structure of EcLpxC bound to L-161,240, providing the first molecular insight into L-161,240 inhibition. Additionally, structural analysis of the EcLpxC/L-161,240 complex together with the EcLpxC/BB-78485 complex reveals an unexpected backbone flipping of the Insert I βa-βb loop in EcLpxC in comparison with previously reported crystal structures of EcLpxC complexes with l-threonyl-hydroxamate-based broad-spectrum inhibitors. Such a conformational switch, which has only been observed in EcLpxC but not in divergent orthologs such as PaLpxC, results in expansion of the active site of EcLpxC, enabling it to accommodate LpxC inhibitors with a variety of head groups, including compounds containing single (R- or S-enantiomers) or double substitutions at the neighboring Cα atom of the hydroxamate warhead group. These results highlight the importance of understanding inherent conformational plasticity of target proteins in lead optimization.
Authors
Lee, C-J; Liang, X; Gopalaswamy, R; Najeeb, J; Ark, ED; Toone, EJ; Zhou, P
MLA Citation
Lee, Chul-Jin, et al. “Structural basis of the promiscuous inhibitor susceptibility of Escherichia coli LpxC..” Acs Chem Biol, vol. 9, no. 1, Jan. 2014, pp. 237–46. Pubmed, doi:10.1021/cb400067g.
URI
https://scholars.duke.edu/individual/pub966278
PMID
24117400
Source
pubmed
Published In
Acs Chem Biol
Volume
9
Published Date
Start Page
237
End Page
246
DOI
10.1021/cb400067g