EDWARD A. DOISY
Department of
Biochemistry & Molecular Biology
EST. 1924
Saint Louis University School of Medicine
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Our Legacy
1 Nobel Laureate
Doisy2 Members, National Academy of Sciences
Doisy, Sly1 Member, National Academy of Medicine
Roth3 Members, American Academy of Arts & Sciences
Doisy, Roth, Shilatifard1 Member, Leopoldina
Kutchan11 Fellows, American Association for the Advancement of Science
Di Cera, Doisy, Elliott, Katzman, Kutchan, Lee, Lodge, McKee, Olson, Shilatifard, Sly5 Members and 1 Fellow, National Academy of Inventors
Chang, Di Cera, Heyduk, Lodge, Pozzi, Sverdrup2 Pew Scholars
Cole, Yap
Message from the Chair
Enrico Di Cera, M.D.
Welcome to our website!
Our department was founded in 1924 by Dr. Edward A. Doisy, discoverer of estrogens and recipient of the 1943 Nobel Prize in Physiology or Medicine for his work on the synthesis of vitamin K.
We have an impressive legacy of excellence, continued by Doisy’s successors Dr. Robert Olson and Dr. William Sly, and by the work of our current outstanding students, postdocs, staff, and faculty.
It is an exciting time to join the BMB family!
Thank you for visiting!
Department Stats
External Grant Expenditures
Publications
Department Members
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What's News
Congratulations to Zachary Foulks, M.D./Ph.D. student in the McCommis lab, on receiving an F30 Predoctoral…
Congratulations to Aidan Antony, Undergraduate Researcher in the Antony Lab, for receiving a 3rd place…
Congratulations to Benedict Offor, Ph.D., Postdoctoral Fellow in the Korolev Lab, for receiving a 3rd…
Congratulations to our BMB faculty members on their promotions. Gabriel Dai, Ph.D., and Kyle McCommis,…
BMB members were honored at the 2026 Scholarly Works and Grant Winners Reception sponsored by the…
Department Committees
Doisy Fund
- Yuna Ayala, Ph.D.
- Ángel Baldán, Ph.D.
- Enrico Di Cera, M.D., Chair
- Kathleen E. Doisy, M.S.
- Krista Lentine, M.D., Ph.D.
- LaChina McCoy
- Ratna Ray, Ph.D.
- Eleonore Stump, Ph.D.
Instrumentation and Cores
- Edwin Antony, Ph.D.
- Yuna Ayala, Ph.D.
- Ángel Baldán, Ph.D.
- Michelle Brennan, Ph.D., Chair
- Reza Dastvan, Ph.D.
- Nicola Pozzi, Ph.D.
Training
- Madison Adolph, Ph.D., Co-Director of the BMB Graduate Program
- Yuna Ayala, Ph.D., Chair
- Susana Gonzalo, Ph.D.
- Tomasz Heyduk, Ph.D., Co-Director of the BMB Graduate Program
- LaChina McCoy
BMB Faculty Incentives
SLU Incentives
- F&A Rebate: Percentage of F&A rebated to 2-fund
- Non-salary incentive: Half of salary recovered beyond 50% rebated to 2-fund
- Salary bonus from the faculty compensation plan for faculty who have recovered 50% or more of their total compensation from extramural sources as a 3-year rolling average from preceding FYs
Primary BMB Faculty
- Matching of the SLU F&A rebate
- Cash award of $500 for new publications with BMB faculty as the corresponding author in journals with an impact factor greater than 10. Cash award of $500 for the leading author of the publication, if a member of BMB
- Full support of the stipend of Ph.D. and M.D./Ph.D. students for 12 months from the date they pass their qualifying exam
Primary & Secondary BMB Faculty
- Matching of JIT grants from the ICTS
- Student support through the Doisy Scholar Program
Dean Loeb Prize
- Cash award of $600
Click to read more about the Hanau Loeb Prize.
Doisy Scholar Program
Doisy Scholars
Biochemistry Ph.D. and M.D./Ph.D. students may be appointed as Doisy Scholars at any time after passing their qualifying exams.
- Appointment to Doisy Scholar is recommended by the BMB Training Committee and reviewed for approval by the Chair of BMB.
- Doisy Scholarship is an honor reserved for students who have distinguished themselves academically through course work and have achieved scholarly recognition through peer-reviewed publications and poster/oral presentations at meetings or extramural fellowships.
- The stipend and student fees of a Doisy Scholar are supported in full by the BMB Doisy Fund for 24 months.
- The Doisy Scholar will also receive a cash award each year from the BMB Doisy Fund.
Click to read more about our Doisy Scholars.
High Impact Publications
Papers highlighted below were published in journals with an impact factor of 10 or greater.
All papers were published within the past year.
All papers were published within the past year.
Recent Publications
Cryo-EM structure of a methanogen nitrogenase-PII protein supercomplex
Cryo-EM structure of a methanogen nitrogenase-PII protein supercomplex
Nitrogenases are metalloenzymes that catalyse the reduction of atmospheric dinitrogen to ammonia, sustaining the global nitrogen cycle. Although bacterial nitrogenase has been extensively characterized, the architecture and regulation of archaeal nitrogenases have remained unknown despite longstanding evidence of nitrogen fixation in methanogens. Here we report a cryo-electron microscopy structure of a native nitrogenase-PII protein supercomplex from Methanosarcina acetivorans. The structure reveals an assembly of three NifDK heterotetramers bridged by six NifI heterotrimeric PII complexes, which sterically block NifH association and lock the enzyme in an inactive state. The PII complexes show asymmetric binding of ADP and 2-oxoglutarate, coupling nitrogenase inhibition directly to cellular energy and nitrogen status. Addition of 2-oxoglutarate and ATP releases the NifI complexes, stimulating a threefold increase in NifDK activity in vitro. This higher-order architecture identifies a regulatory strategy in methanogens in which PII proteins drive nitrogenase oligomerization to control activity. The finding that nitrogenase activity may be modulated through direct assembly into higher-order structures indicates future directions for the exploration of nitrogenase evolution, regulation and biotechnological applications.
Prothrombin recognition and conformational modulation by anti-thrombin anticoagulant aptamers
Prothrombin recognition and conformational modulation by anti-thrombin anticoagulant aptamers
Disorders of the blood coagulation cascade continue to pose a major clinical challenge, necessitating the development of new therapeutic agents capable of modulating this process. Several oligonucleotide aptamers targeting coagulation factors have been developed, and some are undergoing preclinical or clinical evaluation. Among them, anti-thrombin anticoagulant aptamers are promising dual-targeting agents in that, in addition to inhibiting enzyme activity, they may limit thrombin generation by binding to its precursor, prothrombin. In the present study, combined calorimetric and spectroscopic analyses reveal that these aptamers recognize proexosite I of prothrombin and exosite I of thrombin through broadly similar thermodynamic binding mechanisms. Integration of structural small-angle X-ray scattering (SAXS) studies and limited proteolysis assays shows that aptamer binding to proexosite I alters prothrombin structure, shifting the equilibrium from its more abundant closed form to the open conformation. Taken together, these results support the classification of these aptamers as dual-targeting agents capable of recognizing both thrombin and prothrombin and provide guidance for their continued development as anticoagulant therapeutics.
Structural analysis of the primary specificity of thrombin
Structural analysis of the primary specificity of thrombin
Thrombin has dual trypsin-like and chymotrypsin-like specificity: it prefers substrates carrying Arg at the site of cleavage (P1) in the activation peptide because of the presence of D189 in the primary specificity (S1) site but can also cleave substrates carrying Phe at P1.
Progerin Hinders Autophagy Flux at Its Final Stages in Hutchinson-Gilford Progeria Syndrome Cells, Preventing Its Own Autophagic Degradation
Progerin Hinders Autophagy Flux at Its Final Stages in Hutchinson-Gilford Progeria Syndrome Cells, Preventing Its Own Autophagic Degradation
In Hutchinson-Gilford progeria syndrome (HGPS), dysfunctional autophagy results in the accumulation of progerin, a lamin A mutant variant that alters a plethora of processes, inducing senescence and driving premature aging. Therefore, the elimination of progerin through autophagy restoration emerges as a therapeutic intervention against HGPS. However, a comprehensive study of autophagy flux in HGPS remains to be addressed. In this study, the dynamics of autophagy in HGPS fibroblasts were analyzed utilizing different HGPS cell models and experimental approaches. The autophagy-associated transcriptomic profile was determined, and the autophagy-lysosome axis was comprehensively analyzed. We demonstrated that progerin induces the formation of autophagosomes but impairs their maturation and subsequent fusion with lysosomes. This alteration is attributed in part to the progerin-mediated decreased expression of STX17, a marker of mature autophagosomes, and LAMP1, a membrane lysosomal protein, as well as the presence of defective lysosomes. In line with this, the rescue of STX17 and LAMP1 expression improved autophagy flux. Interestingly, treatment of HGPS fibroblasts with Selinexor, an autophagy activator, elicited nuclear accumulation of TFEB and enhanced lysosomal biogenesis and function, thereby activating autophagy. Selinexor treatment improved both autophagosome maturation and autophagosome-lysosome fusion, which ultimately led to effective autophagic degradation of progerin. In summary, progerin impedes proper autophagy flux, thus preventing its own autophagic degradation, which underscores the relevance of targeting the autophagy-lysosome pathway to counteract the toxic accumulation of progerin.
CRISPR RNA architecture steers Cas9 catalysis and fidelity via a guide repeat clasp motif
CRISPR RNA architecture steers Cas9 catalysis and fidelity via a guide repeat clasp motif
A widely adopted modification of CRISPR-Cas9 is fusion of the naturally occurring two-component dual guide RNA (dgRNA) to create an artificial single guide RNA (sgRNA). Here we find that these guide architectures induce differential catalysis, gene editing, and specificity. Spacer sequence and RNA structural features could not predict guide architecture editing preference across 255 endogenous targets. We used cryo-EM and molecular dynamics to identify a new Cas9 structural motif, the guide repeat clasp (GRC), that checks guide RNA repeat structure and coordinates with R-loop sensing checkpoint mechanisms to help license cleavage. Limited mutagenesis of GRC residues significantly altered Cas9 editing and specificity, supporting a key role in catalysis. To further understand the role of the GRC and guide RNA repeat dynamics, we created guide repeat-truncated sgRNAs, or grtRNAs, which conferred some dgRNA properties onto sgRNA, including generally lower off-target editing for targets with PAM-proximal mismatches. dgRNAs and grtRNAs could be combined with a new high-fidelity Cas9 variant called ZiFY, rationally designed to reduce editing of targets with PAM-distal mismatches, to generate broader mismatched target discrimination. These results uncover a previously unknown mechanism that steers Cas9 catalysis and demonstrate the potential to improve Cas9 fidelity by modulating guide repeat interactions.
Proton-coupled alternating access in a versatile mycobacterial Spns drug transporter
Proton-coupled alternating access in a versatile mycobacterial Spns drug transporter
Spns transporters are a mechanistically distinct branch of the major facilitator superfamily that regulate lipid transport, lysosomal homeostasis, immunity and disease, yet how the conserved Spns fold integrates protonation, substrate binding and alternating access to support chemically and directionally diverse transport activities remains unresolved. Here, we combine DEER spectroscopy in lipid nanodiscs with DEER- and AlphaFold-guided modeling to define the conformational landscape of the homolog Spns. Protonation shifts Spns toward an inward-facing state, whereas deprotonation favors a broader outward-facing ensemble through coordinated remodeling of intracellular and extracellular gates. These transitions are governed by membrane-embedded protonation switches and proton-sensing networks, while the substrate-binding cavity shows distinct proton sensitivity and weaker cooperativity. Hydrophilic cationic substrates, capreomycin and ethidium bromide, stabilize the outward-facing state, consistent with efflux antiport, whereas lipophilic compounds, including rifampicin, epicholesterol and selected phospholipids, favor the inward-facing state, suggesting uptake or allosteric stabilization. Thus, conserved proton-coupling elements can power opposing transport modes, revealing the mechanistic versatility of the Spns fold and its therapeutic potential.
Structural insights into the exosite-mediated activation of factor IX by factor XIa using cryogenic electron microscopy
Structural insights into the exosite-mediated activation of factor IX by factor XIa using cryogenic electron microscopy
Factor (F)XI occupies a unique and clinically significant niche, bridging the tissue factor-driven and contact-driven coagulation pathways. Irrespective of the trigger, activated factor XI (FXIa) contributes to clotting by activating FIX. Biochemical studies established that this reaction requires the membrane-binding FIX-Gla domain to engage an exosite on the FXIa Apple 3 (A3) domain, which only becomes available upon FXI activation. Structural data for FXIa, FIX, FIXaβ and the FXIa:FIX complex are lacking; current understanding relies on zymogen FXI crystal structures and homology modeling of FXIa after kallikrein.
Dual-Functional Self-Assembled Nanoparticles for Synergistic Photodynamic Therapy and Antimetastatic Treatment of Colorectal Cancer
Dual-Functional Self-Assembled Nanoparticles for Synergistic Photodynamic Therapy and Antimetastatic Treatment of Colorectal Cancer
Colorectal cancer (CRC) is a major clinical challenge due to high metastasis and therapy resistance. Photodynamic therapy (PDT) offers precise tumor ablation but lacks sustained anti-metastatic activity. Peptidic urokinase-type plasminogen activator (uPA) inhibitors suppress metastasis but suffer from short half-life and poor tumor retention. This study aimed to develop a dual-functional self-assembled nanoplatform integrating PDT and selective uPA inhibition for synergistic CRC treatment. : We designed and synthesized a conjugate by linking pyropheophorbide-a (PPA) with uPA-targeted cyclic peptide IG2, which self-assembled into nanoparticles (PINPs). Physicochemical properties, reactive oxygen species (ROS) generation, and uPA inhibitory activity were characterized. In vitro studies included cellular uptake, cytotoxicity, and invasion assays. In vivo therapeutic efficacy was evaluated in subcutaneous CT26 tumor models and lung metastasis models, with biosafety assessed by body weight monitoring. : PINPs exhibited uniform spherical nanostructure, prolonged blood circulation, and enhanced tumor accumulation via the enhanced permeability and retention (EPR) effect. Under 680 nm irradiation, PINPs generated robust ROS and induced tumor cell apoptosis. PINPs potently inhibited uPA activity and suppressed tumor cell invasion. In vivo, PINPs plus PDT achieved significant tumor growth inhibition (73.6%) and strong anti-metastatic efficacy (60.7%), superior to free IG2. No obvious systemic toxicity was observed. : The dual-functional PINPs achieve short-term acute tumor ablation via PDT and sustained anti-metastatic potential via uPA inhibition within the tested observation windows, with favorable biosafety. This carrier-free self-assembly strategy provides proof-of-concept validation and a generalizable design paradigm for developing synergistic anti-metastatic nanotherapeutics against metastatic CRC.
A toxic STING-SAMHD1 axis drives replication stress in progeria and cancer cells
A toxic STING-SAMHD1 axis drives replication stress in progeria and cancer cells
STING is an innate immune adaptor, classically activated by cytosolic DNA via cGAS-cGAMP to induce interferon signaling. Recent studies reveal that STING participates in non-canonical signaling pathways and localizes to the nucleus, where its functions remain poorly understood. In Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging disease caused by expression of the lamin-A mutant protein 'progerin', STING accumulates in the nucleus and drives chronic inflammation. Here, we show that replication stress is a trigger of STING nuclear accumulation and chromatin binding. In addition, we uncover that STING binds to nascent DNA and promotes replication stress in progeria and tumor cells. Mechanistically, STING causes replication fork slowing and stalling by limiting dNTPs availability. Upon fork stalling, STING hinders replication fork protection/stability by facilitating MRE11-mediated nascent DNA degradation (NDD). Importantly, STING's contribution to dNTP depletion and NDD is mediated by SAMHD1. Depletion of SAMHD1 phenocopies STING abrogation in reducing replication stress in progeria cells, and rescues replication fork speed and stability in STING-expressing tumor cells. These findings define a pathological STING-SAMHD1 axis that drives replication stress and genome instability in both progeria cells and tumor cells with elevated STING activity, uncovering a feedforward loop between innate immune signaling and impaired DNA replication.
Workflow for Accurate Measurement of PDI Reductase Kinetics Using a Fluorescent Disulfide Substrate
Workflow for Accurate Measurement of PDI Reductase Kinetics Using a Fluorescent Disulfide Substrate
Protein disulfide isomerase (PDI) is essential for oxidative protein folding, proteostasis, and redox regulation and has become a promising target for thromboinflammation, cancer, and neurodegenerative disorders. Fluorogenic disulfide substrates like Bodipy FL L-cystine (BDSS) are essential for mechanistic studies but have low affinity for PDI, necessitating high micromolar concentrations to measure Michaelis-Menten kinetics. These conditions can lead to optical artifacts, requiring development of correction methods to enable rigorous characterization of PDI inhibitors and allosteric modulators. Here, we present a simple workflow for correcting fluorescence quenching during BDSS reduction assays and provide an example of its utility with two allosteric modulators.
