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1.
Structure ; 2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38908376

ABSTRACT

The epidermal growth factor receptor (EGFR) is a well-known oncogenic driver in lung and other cancers. In glioblastoma multiforme (GBM), the EGFR deletion variant III (EGFRvIII) is frequently found alongside EGFR amplification. Agents targeting the EGFR axis have shown limited clinical benefits in GBM and the role of EGFRvIII in GBM is poorly understood. To shed light on the role of EGFRvIII and its potential as a therapeutic target, we determined X-ray crystal structures of a monomeric EGFRvIII extracellular region (ECR). The EGFRvIII ECR resembles the unliganded conformation of EGFR, including the orientation of the C-terminal region of domain II. Domain II is mostly disordered, but the ECR structure is compact. We selected a nanobody with preferential binding to EGFRvIII relative to EGFR and structurally defined an epitope on domain IV that is occluded in the unliganded intact EGFR. These findings suggest new avenues for EGFRvIII targeting in GBM.

2.
J Cell Physiol ; 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38924572

ABSTRACT

There is no doubt that navigating academia is a formidable challenge, particularly for those from underrepresented backgrounds who face additional barriers at every turn. In such an environment, efforts to create learning and training environments that are diverse, equitable, and inclusive can feel like an uphill battle. We believe that harnessing the power of artificial intelligence (AI) tools can help in leveling the playing field. While AI cannot supplant the need for supportive mentorship, it can serve as a vital supplement, offering guidance and assistance to those who may lack access to adequate avenues of support. Embracing AI in this context should not be stigmatized, as it may represent a vital lifeline for underrepresented individuals who often face systemic biases while forging their own paths in pursuit of success and belonging in academia. AI tools should not be gatekept from these individuals, particularly by those in positions of power and privilege within the scientific community. Instead, we argue, institutions should make a strong commitment to educating their community members on how to ethically harness these tools.

3.
Nat Cell Biol ; 26(1): 11-12, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38228832
5.
Trends Mol Med ; 28(9): 707-709, 2022 09.
Article in English | MEDLINE | ID: mdl-35868960

ABSTRACT

Diversity, equity, and inclusion (DEI) efforts have increased drastically as companies and institutions recognize their value in fostering innovative ideas for success. Individuals trained in these efforts can impart their knowledge and expertise in consultation, but this transaction should be mutually beneficial. Here, we provide recommendations to maximize consulting opportunities.


Subject(s)
Referral and Consultation , Humans
6.
Trends Cancer ; 8(8): 620-622, 2022 08.
Article in English | MEDLINE | ID: mdl-35672243

ABSTRACT

Shadow mentoring relationships are those outside of traditional mentoring roles and are an unseen yet critical component of trainee retention that is rarely acknowledged. In this paper, we detail the costs and benefits of shadow mentoring and propose mechanisms to ensure that shadow mentoring is acknowledged as a vital contribution to scientific communities.


Subject(s)
Mentoring , Cost-Benefit Analysis , Humans , Mentors
7.
Pathog Dis ; 79(6)2021 07 28.
Article in English | MEDLINE | ID: mdl-34283236

ABSTRACT

Mentoring is a developmental experience intended to increase the willingness to learn and establish credibility while building positive relationships through networking. In this commentary, we focus on intentional mentoring for underrepresented mentees, including individuals that belong to minority racial, ethnic and gender identity groups in Science, Technology, Engineering, Mathematics and Medicine (STEMM) fields. Intentional mentoring is the superpower action necessary for developing harmony and comprehending the purpose and value of the mentor/mentee relationship. Regardless of a mentor's career stage, we believe the strategies discussed may be used to create a supportive and constructive mentorship environment; thereby improving the retention rates of underrepresented mentees within the scientific community.


Subject(s)
Communication , Interprofessional Relations , Mentoring , Mentors , Humans , Trust
8.
Cell ; 184(4): 851-853, 2021 02 18.
Article in English | MEDLINE | ID: mdl-33606982

ABSTRACT

Dr. Chrystal Starbird is the winner of the first Rising Black Scientist Award for a post-graduate scholar. For this award, we asked emerging Black scientists to tell us about the experiences that sparked their journey in the life sciences. This is her story.


Subject(s)
Racism , Universities , Black or African American , Awards and Prizes , Humans
9.
J Biol Chem ; 291(6): 2904-16, 2016 Feb 05.
Article in English | MEDLINE | ID: mdl-26644464

ABSTRACT

Escherichia coli harbors two highly conserved homologs of the essential mitochondrial respiratory complex II (succinate:ubiquinone oxidoreductase). Aerobically the bacterium synthesizes succinate:quinone reductase as part of its respiratory chain, whereas under microaerophilic conditions, the quinol:fumarate reductase can be utilized. All complex II enzymes harbor a covalently bound FAD co-factor that is essential for their ability to oxidize succinate. In eukaryotes and many bacteria, assembly of the covalent flavin linkage is facilitated by a small protein assembly factor, termed SdhE in E. coli. How SdhE assists with formation of the covalent flavin bond and how it binds the flavoprotein subunit of complex II remain unknown. Using photo-cross-linking, we report the interaction site between the flavoprotein of complex II and the SdhE assembly factor. These data indicate that SdhE binds to the flavoprotein between two independently folded domains and that this binding mode likely influences the interdomain orientation. In so doing, SdhE likely orients amino acid residues near the dicarboxylate and FAD binding site, which facilitates formation of the covalent flavin linkage. These studies identify how the conserved SdhE assembly factor and its homologs participate in complex II maturation.


Subject(s)
Electron Transport Complex II/metabolism , Escherichia coli Proteins/metabolism , Escherichia coli/metabolism , Flavin-Adenine Dinucleotide/metabolism , Electron Transport Complex II/genetics , Escherichia coli/genetics , Escherichia coli Proteins/genetics , Flavin-Adenine Dinucleotide/genetics
10.
Biochemistry ; 54(22): 3514-27, 2015 Jun 09.
Article in English | MEDLINE | ID: mdl-25928369

ABSTRACT

Response regulator signaling proteins and phosphatases of the haloacid dehalogenase (HAD) superfamily share strikingly similar folds, active site geometries, and reaction chemistry. Proteins from both families catalyze the transfer of a phosphoryl group from a substrate to one of their own aspartyl residues, and subsequent hydrolysis of the phosphoprotein. Notable differences include an additional Asp that functions as an acid/base catalyst and an active site well-structured prior to phosphorylation in HAD phosphatases. Both features contribute to reactions substantially faster than those for response regulators. To investigate mechanisms underlying the functional differences between response regulators and HAD phosphatases, we characterized five double mutants of the response regulator CheY designed to mimic HAD phosphatases. Each mutant contained the extra Asp paired with a phosphatase-inspired substitution to potentially position the Asp properly. Only CheY DR (Arg as the anchor) exhibited enhanced rates of both autophosphorylation with phosphoramidate and autodephosphorylation compared to those of wild-type CheY. Crystal structures of CheY DR complexed with MoO4(2-) or WO4(2-) revealed active site hydrogen bonding networks similar to those in HAD·substrate complexes, with the extra Asp positioned for direct interaction with the leaving group (phosphorylation) or nucleophile (dephosphorylation). However, CheY DR reaction kinetics did not exhibit the pH sensitivities expected for acid/base catalysis. Biochemical analysis indicated CheY DR had an enhanced propensity to adopt the active conformation without phosphorylation, but a crystal structure revealed unphosphorylated CheY DR was not locked in the active conformation. Thus, the enhanced reactivity of CheY DR reflected partial acquisition of catalytic and structural features of HAD phosphatases.


Subject(s)
Bacterial Proteins/chemistry , Escherichia coli/enzymology , Hydrolases , Membrane Proteins/chemistry , Phosphoprotein Phosphatases/chemistry , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Crystallography, X-Ray , Escherichia coli/genetics , Escherichia coli Proteins , Hydrogen-Ion Concentration , Kinetics , Membrane Proteins/genetics , Membrane Proteins/metabolism , Methyl-Accepting Chemotaxis Proteins , Mutation , Phosphoprotein Phosphatases/genetics , Phosphoprotein Phosphatases/metabolism , Phosphorylation/physiology
11.
Nat Chem Biol ; 10(5): 392-9, 2014 May.
Article in English | MEDLINE | ID: mdl-24657930

ABSTRACT

Concatenation of engineered biocatalysts into multistep pathways markedly increases their utility, but the development of generalizable assembly methods remains a major challenge. Herein we evaluate 'bioretrosynthesis', which is an application of the retrograde evolution hypothesis, for biosynthetic pathway construction. To test bioretrosynthesis, we engineered a pathway for synthesis of the antiretroviral nucleoside analog didanosine (2',3'-dideoxyinosine). Applying both directed evolution- and structure-based approaches, we began pathway construction with a retro-extension from an engineered purine nucleoside phosphorylase and evolved 1,5-phosphopentomutase to accept the substrate 2,3-dideoxyribose 5-phosphate with a 700-fold change in substrate selectivity and threefold increased turnover in cell lysate. A subsequent retrograde pathway extension, via ribokinase engineering, resulted in a didanosine pathway with a 9,500-fold change in nucleoside production selectivity and 50-fold increase in didanosine production. Unexpectedly, the result of this bioretrosynthetic step was not a retro-extension from phosphopentomutase but rather the discovery of a fortuitous pathway-shortening bypass via the engineered ribokinase.


Subject(s)
Didanosine/metabolism , Biocatalysis , Directed Molecular Evolution , Enzymes/metabolism , Models, Molecular
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