Crystal structure of native Anopheles gambiae
 serpin-2, a negative regulator of melanization in mosquitoes

Serine protease inhibitors (serpins) in insects function within development, wound healing and immunity. The genome of the African malaria vector,Anopheles gambiae, encodes 23 distinct serpin proteins, several of which are implicated in disease-relevant physiological responses.A. gambiaeserpin 18 (SRPN18) was previously categorized as non-inhibitory based on the sequence of its reactive-center loop (RCL), a region responsible for targeting and initiating protease inhibition. The crystal structure ofA. gambiaeSRPN18 was determined to a resolution of 1.45 Å, including nearly the entire RCL in one of the two molecules in the asymmetric unit. The structure reveals that the SRPN18 RCL is extremely short and constricted, a feature associated with noncanonical inhibitors or non-inhibitory serpin superfamily members. Furthermore, the SRPN18 RCL does not contain a suitable protease target site and contains a large number of prolines. The SRPN18 structure therefore reveals a unique RCL architecture among the highly conserved serpin fold.

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Crystal structure of Npun_R1517, a putative negative regulator of heterocyst differentiation fromNostoc punctiformePCC 73102

Proteins Structure Function and Bioinformatics ◽

10.1002/prot.22308 ◽

2009 ◽

Vol 74 (3) ◽

pp. 794-798 ◽

Cited By ~ 4

Author(s):

Shuisong Ni ◽

Matthew M. Benning ◽

Matthew J. Smola ◽

Erik A. Feldmann ◽

Michael A. Kennedy

Keyword(s):

Crystal Structure ◽

Negative Regulator ◽

Heterocyst Differentiation

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X-ray Crystal Structure of the Bacterial Conjugation Factor PsiB, a Negative Regulator of RecA

Journal of Biological Chemistry ◽

10.1074/jbc.m110.152298 ◽

2010 ◽

Vol 285 (40) ◽

pp. 30615-30621 ◽

Cited By ~ 3

Author(s):

Vessela Petrova ◽

Kenneth A. Satyshur ◽

Nicholas P. George ◽

Darrell McCaslin ◽

Michael M. Cox ◽

...

Keyword(s):

Crystal Structure ◽

Negative Regulator ◽

Bacterial Conjugation ◽

X Ray

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Crystal structure of PhoU fromPseudomonas aeruginosa, a negative regulator of the Pho regulon

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273315096503 ◽

2015 ◽

Vol 71 (a1) ◽

pp. s231-s231

Author(s):

Sang Jae Lee ◽

Bong-Jin Lee ◽

Se Won Suh

Keyword(s):

Crystal Structure ◽

Negative Regulator ◽

Pho Regulon

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Crystal structure of acetylcholinesterase catalytic subunits of the malaria vector Anopheles gambiae

Insect Science ◽

10.1111/1744-7917.12450 ◽

2017 ◽

Vol 25 (4) ◽

pp. 721-724 ◽

Cited By ~ 9

Author(s):

Qian Han ◽

Dawn M. Wong ◽

Howard Robinson ◽

Haizhen Ding ◽

Polo C. H. Lam ◽

...

Keyword(s):

Crystal Structure ◽

Anopheles Gambiae ◽

Malaria Vector ◽

Catalytic Subunits

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The crystal structure of an odorant binding protein from Anopheles gambiae: Evidence for a common ligand release mechanism

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2005.10.191 ◽

2006 ◽

Vol 339 (1) ◽

pp. 157-164 ◽

Cited By ~ 111

Author(s):

Mark Wogulis ◽

Tania Morgan ◽

Yuko Ishida ◽

Walter S. Leal ◽

David K. Wilson

Keyword(s):

Crystal Structure ◽

Anopheles Gambiae ◽

Binding Protein ◽

Odorant Binding Protein ◽

Release Mechanism ◽

Odorant Binding

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Discovery and Structure-Based Design of Macrocyclic Peptides Targeting STUB1

10.26434/chemrxiv-2021-1108b ◽

2021 ◽

Author(s):

Simon Ng ◽

Alexander Brueckner ◽

Soheila Bahmanjah ◽

Qiaolin Deng ◽

Jennifer Johnston ◽

...

Keyword(s):

Crystal Structure ◽

Interferon Gamma ◽

Negative Regulator ◽

Malignant Cells ◽

Target Validation ◽

Exposed Region ◽

Macrocyclic Peptides ◽

Cellular Permeability ◽

Hydrophilic Solvent ◽

Further Development

STIP1 homology and U-Box containing protein 1 (STUB1) plays a key role in maintaining cell health during stress and aging. Recent evidence suggested STUB1 also helps regulate immunity with the potential of clearing malignant cells. Indeed, we and others have shown that STUB1 is a pivotal negative regulator of interferon gamma sensing – a process critical to the immunosurveillance of tumors and pathogens. Thus far, investigation of STUB1’s role relies mostly on genetic approaches as pharmacological inhibitors of this protein are lacking. Identification of a STUB1 tool compound is important as it would allow therapeutically relevant target validation in a broader sense. Accordingly, we leveraged phage display and computational modeling to identify and refine STUB1 binders. Screening of >10E9 macrocyclic peptides resulted in several conserved motifs as well as structurally diverse leads. Co-crystal structure of the peptide hit and STUB1 has enabled us to employ structure-based in silico design for further optimization. Of the modifications employed, replacing the hydrophilic solvent-exposed region of the macrocyclic peptides with a hydrophobic scaffold improved cellular permeability, while the binding conformation was maintained. Further substitution of the permeability-limiting terminal aspartic acid with a tetrazole bioisostere retained the binding to certain extent while improving permeability, suggesting a path forward. The current lead, although not optimal for cellular study, provides a valuable template for further development into selective tool compounds for STUB1 to enable target validation.

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