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Article: XDSGUI

Brehm, Wolfgang / Triviño, Josep / Krahn, Juno M / Usón, Isabel / Diederichs, Kay

2023 Volume 56, Issue Pt 5, Page(s) 1585–1594

Abstract: ... ...

Abstract	XDSGUI
Language	English
Publishing date	2023-09-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2020879-0
ISSN	1600-5767 ; 0021-8898
ISSN (online)	1600-5767
ISSN	0021-8898
DOI	10.1107/S1600576723007057
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Article ; Online: Targeting the Structural Maturation Pathway of HIV-1 Reverse Transcriptase.

Kirby, Thomas W / Gabel, Scott A / DeRose, Eugene F / Perera, Lalith / Krahn, Juno M / Pedersen, Lars C / London, Robert E

Biomolecules

2023 Volume 13, Issue 11

Abstract: Formation of active HIV-1 reverse transcriptase (RT) proceeds via a structural maturation process that involves subdomain rearrangements and formation of an asymmetric p66/p66' homodimer. These studies were undertaken to evaluate whether the information ... ...

Abstract	Formation of active HIV-1 reverse transcriptase (RT) proceeds via a structural maturation process that involves subdomain rearrangements and formation of an asymmetric p66/p66' homodimer. These studies were undertaken to evaluate whether the information about this maturation process can be used to identify small molecule ligands that retard or interfere with the steps involved. We utilized the isolated polymerase domain, p51, rather than p66, since the initial subdomain rearrangements are largely limited to this domain. Target sites at subdomain interfaces were identified and computational analysis used to obtain an initial set of ligands for screening. Chromatographic evaluations of the p51 homodimer/monomer ratio support the feasibility of this approach. Ligands that bind near the interfaces and a ligand that binds directly to a region of the fingers subdomain involved in subunit interface formation were identified, and the interactions were further characterized by NMR spectroscopy and X-ray crystallography. Although these ligands were found to reduce dimer formation, further efforts will be required to obtain ligands with higher binding affinity. In contrast with previous ligand identification studies performed on the RT heterodimer, subunit interface surfaces are solvent-accessible in the p51 and p66 monomers, making these constructs preferable for identification of ligands that directly interfere with dimerization.
MeSH term(s)	Ligands ; HIV Reverse Transcriptase/chemistry ; Dimerization ; Magnetic Resonance Spectroscopy
Chemical Substances	reverse transcriptase, Human immunodeficiency virus 1 (EC 2.7.7.-) ; Ligands ; HIV Reverse Transcriptase (EC 2.7.7.49)
Language	English
Publishing date	2023-11-01
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom13111603
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Article ; Online: Author Correction: Structural basis for pre-tRNA recognition and processing by the human tRNA splicing endonuclease complex.

Hayne, Cassandra K / Butay, Kevin John U / Stewart, Zachary D / Krahn, Juno M / Perera, Lalith / Williams, Jason G / Petrovitch, Robert M / Deterding, Leesa J / Matera, A Gregory / Borgnia, Mario J / Stanley, Robin E

Nature structural & molecular biology

2024 Volume 31, Issue 2, Page(s) 390

Language	English
Publishing date	2024-01-09
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/s41594-024-01213-w
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Article ; Online: Heparan sulfate selectively inhibits the collagenase activity of cathepsin K.

Zhang, Xiaoxiao / Luo, Yin / Hao, Huanmeng / Krahn, Juno M / Su, Guowei / Dutcher, Robert / Xu, Yongmei / Liu, Jian / Pedersen, Lars C / Xu, Ding

Matrix biology : journal of the International Society for Matrix Biology

2024

Abstract: Cathepsin K (CtsK) is a cysteine protease with potent collagenase activity. CtsK is highly expressed by bone-resorbing osteoclasts and plays an essential role in resorption of bone matrix. Although CtsK is known to bind heparan sulfate (HS), the ... ...

Abstract	Cathepsin K (CtsK) is a cysteine protease with potent collagenase activity. CtsK is highly expressed by bone-resorbing osteoclasts and plays an essential role in resorption of bone matrix. Although CtsK is known to bind heparan sulfate (HS), the structural details of the interaction, and how HS regulates the biological functions of CtsK, remains largely unknown. In this report, we discovered that HS is a multifaceted regulator of the structure and function of CtsK. Structurally, HS forms a highly stable complex with CtsK and induces its dimerization. Co-crystal structures of CtsK with bound HS oligosaccharides reveal the location of the HS binding site and suggest how HS may support dimerization. Functionally, HS plays a dual role in regulating the enzymatic activity of CtsK. While it preserves the peptidase activity of CtsK by stabilizing its active conformation, it inhibits the collagenase activity of CtsK in a sulfation level-dependent manner. These opposing effects can be explained by our finding that the HS binding site is remote from the active site, which allows HS to specifically inhibit the collagenase activity without affecting the peptidase activity. At last, we show that structurally defined HS oligosaccharides effectively block osteoclast resorption of bone in vitro without inhibiting osteoclast differentiation, which suggests that HS-based oligosaccharide might be explored as a new class of selective CtsK inhibitor for many diseases involving exaggerated bone resorption.
Language	English
Publishing date	2024-03-26
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1183793-7
ISSN	1569-1802 ; 0945-053X
ISSN (online)	1569-1802
ISSN	0945-053X
DOI	10.1016/j.matbio.2024.03.005
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Article: Heparan sulfate selectively inhibits the collagenase activity of cathepsin K.

Zhang, Xiaoxiao / Luo, Yin / Hao, Huanmeng / Krahn, Juno M / Su, Guowei / Dutcher, Robert / Xu, Yongmei / Liu, Jian / Pedersen, Lars C / Xu, Ding

bioRxiv : the preprint server for biology

2024

Abstract: Cathepsin K (CtsK) is a cysteine protease with potent collagenase activity. CtsK is highly expressed by bone-resorbing osteoclasts and plays an essential role in bone remodeling. Although CtsK is known to bind heparan sulfate (HS), the structural details ...

Abstract	Cathepsin K (CtsK) is a cysteine protease with potent collagenase activity. CtsK is highly expressed by bone-resorbing osteoclasts and plays an essential role in bone remodeling. Although CtsK is known to bind heparan sulfate (HS), the structural details of the interaction, and how HS ultimately regulates the biological functions of CtsK, remains largely unknown. In this report, we determined that CtsK preferably binds to larger HS oligosaccharides, such as dodecasaccharides (12mer), and that the12mer can induce monomeric CtsK to form a stable dimer in solution. Interestingly, while HS has no effect on the peptidase activity of CtsK, it greatly inhibits the collagenase activity of CtsK in a manner dependent on sulfation level. By forming a complex with CtsK, HS was able to preserve the full peptidase activity of CtsK for prolonged periods, likely by stabilizing its active conformation. Crystal structures of Ctsk with a bound 12mer, alone and in the presence of the endogenous inhibitor cystatin-C reveal the location of HS binding is remote from the active site. Mutagenesis based on these complex structures identified 6 basic residues of Ctsk that play essential roles in mediating HS-binding. At last, we show that HS 12mers can effectively block osteoclast resorption of bone
Language	English
Publishing date	2024-01-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.05.574350
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Article: Method for the structural analysis of Twinkle mitochondrial DNA helicase by cryo-EM

Riccio, Amanda A. / Bouvette, Jonathan / Longley, Matthew J. / Krahn, Juno M. / Borgnia, Mario J. / Copeland, William C.

Methods. 2022 June 27,

2022

Abstract: The mitochondrial replisome replicates the 16.6 kb mitochondria DNA (mtDNA). The proper functioning of this multicomponent protein complex is vital for the integrity of the mitochondrial genome. One of the critical protein components of the mitochondrial ...

Abstract	The mitochondrial replisome replicates the 16.6 kb mitochondria DNA (mtDNA). The proper functioning of this multicomponent protein complex is vital for the integrity of the mitochondrial genome. One of the critical protein components of the mitochondrial replisome is the Twinkle helicase, a member of the Superfamily 4 (SF4) helicases. Decades of research has uncovered common themes among SF4 helicases including self-assembly, ATP-dependent translocation, and formation of protein–protein complexes. Some of the molecular details of these processes are still unknown for the mitochondria SF4 helicase, Twinkle. Here, we describe a protocol for expression, purification, and single-particle cryo-electron microscopy of the Twinkle helicase clinical variant, W315L, which resulted in the first high-resolution structure of Twinkle helicase. The methods described here serve as an adaptable protocol to support future high-resolution studies of Twinkle helicase or other SF4 helicases.
Keywords	DNA helicases ; cryo-electron microscopy ; mitochondria ; mitochondrial DNA ; mitochondrial genome
Language	English
Dates of publication	2022-0627
Publishing place	Elsevier Inc.
Document type	Article
Note	Pre-press version
ZDB-ID	1066584-5
ISSN	1095-9130 ; 1046-2023
ISSN (online)	1095-9130
ISSN	1046-2023
DOI	10.1016/j.ymeth.2022.06.012
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 3239: Show issues

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Article ; Online: Predicting tumor response to drugs based on gene-expression biomarkers of sensitivity learned from cancer cell lines.

Li, Yuanyuan / Umbach, David M / Krahn, Juno M / Shats, Igor / Li, Xiaoling / Li, Leping

BMC genomics

2021 Volume 22, Issue 1, Page(s) 272

Abstract: Background: Human cancer cell line profiling and drug sensitivity studies provide valuable information about the therapeutic potential of drugs and their possible mechanisms of action. The goal of those studies is to translate the findings from in vitro ...

Abstract	Background: Human cancer cell line profiling and drug sensitivity studies provide valuable information about the therapeutic potential of drugs and their possible mechanisms of action. The goal of those studies is to translate the findings from in vitro studies of cancer cell lines into in vivo therapeutic relevance and, eventually, patients' care. Tremendous progress has been made. Results: In this work, we built predictive models for 453 drugs using data on gene expression and drug sensitivity (IC Conclusions: We demonstrated that our approach can predict drugs that 1) are tumor-type specific; 2) elicit higher sensitivity from tumor compared to corresponding normal tissue; 3) elicit differential sensitivity across breast cancer subtypes. If validated, our prediction could have relevance for preclinical drug testing and in phase I clinical design.
MeSH term(s)	Biomarkers ; Biomarkers, Tumor/genetics ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Cell Line, Tumor ; Gene Expression ; Gene Expression Profiling ; Humans ; Pharmaceutical Preparations
Chemical Substances	Biomarkers ; Biomarkers, Tumor ; Pharmaceutical Preparations
Language	English
Publishing date	2021-04-15
Publishing country	England
Document type	Journal Article
ISSN	1471-2164
ISSN (online)	1471-2164
DOI	10.1186/s12864-021-07581-7
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Article ; Online: Molecular basis for processing of topoisomerase 1-triggered DNA damage by Apn2/APE2.

Williams, Jessica S / Wojtaszek, Jessica L / Appel, Denise C / Krahn, Juno / Wallace, Bret D / Walsh, Evan / Kunkel, Thomas A / Williams, R Scott

Cell reports

2022 Volume 41, Issue 1, Page(s) 111448

Abstract: Topoisomerase 1 (Top1) incises DNA containing ribonucleotides to generate complex DNA lesions that are resolved by APE2 (Apn2 in yeast). How Apn2 engages and processes this DNA damage is unclear. Here, we report X-ray crystal structures and biochemical ... ...

Abstract	Topoisomerase 1 (Top1) incises DNA containing ribonucleotides to generate complex DNA lesions that are resolved by APE2 (Apn2 in yeast). How Apn2 engages and processes this DNA damage is unclear. Here, we report X-ray crystal structures and biochemical analysis of Apn2-DNA complexes to demonstrate how Apn2 frays and cleaves 3' DNA termini via a wedging mechanism that facilitates 1-6 nucleotide endonucleolytic cleavages. APN2 deletion and DNA-wedge mutant Saccharomyces cerevisiae strains display mutator phenotypes, cell growth defects, and sensitivity to genotoxic stress in a ribonucleotide excision repair (RER)-defective background harboring a high density of Top1-incised ribonucleotides. Our data implicate a wedge-and-cut mechanism underpinning the broad-specificity Apn2 nuclease activity that mitigates mutagenic and genome instability phenotypes caused by Top1 incision at genomic ribonucleotides incorporated by DNA polymerase epsilon.
MeSH term(s)	DNA ; DNA Damage ; DNA Polymerase II/genetics ; DNA Repair ; DNA Topoisomerases, Type I/metabolism ; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; Ribonucleotides/chemistry ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
Chemical Substances	Ribonucleotides ; Saccharomyces cerevisiae Proteins ; DNA (9007-49-2) ; DNA Polymerase II (EC 2.7.7.7) ; APN2 protein, S cerevisiae (EC 4.2.99.18) ; DNA-(Apurinic or Apyrimidinic Site) Lyase (EC 4.2.99.18) ; TOP1 protein, S cerevisiae (EC 5.99.1.1) ; DNA Topoisomerases, Type I (EC 5.99.1.2)
Language	English
Publishing date	2022-10-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.111448
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Article ; Online: Flipped over U: structural basis for dsRNA cleavage by the SARS-CoV-2 endoribonuclease.

Frazier, Meredith N / Wilson, Isha M / Krahn, Juno M / Butay, Kevin John / Dillard, Lucas B / Borgnia, Mario J / Stanley, Robin E

Nucleic acids research

2022 Volume 50, Issue 14, Page(s) 8290–8301

Abstract: Coronaviruses generate double-stranded (ds) RNA intermediates during viral replication that can activate host immune sensors. To evade activation of the host pattern recognition receptor MDA5, coronaviruses employ Nsp15, which is a uridine-specific ... ...

Abstract	Coronaviruses generate double-stranded (ds) RNA intermediates during viral replication that can activate host immune sensors. To evade activation of the host pattern recognition receptor MDA5, coronaviruses employ Nsp15, which is a uridine-specific endoribonuclease. Nsp15 is proposed to associate with the coronavirus replication-transcription complex within double-membrane vesicles to cleave these dsRNA intermediates. How Nsp15 recognizes and processes dsRNA is poorly understood because previous structural studies of Nsp15 have been limited to small single-stranded (ss) RNA substrates. Here we present cryo-EM structures of SARS-CoV-2 Nsp15 bound to a 52nt dsRNA. We observed that the Nsp15 hexamer forms a platform for engaging dsRNA across multiple protomers. The structures, along with site-directed mutagenesis and RNA cleavage assays revealed critical insight into dsRNA recognition and processing. To process dsRNA Nsp15 utilizes a base-flipping mechanism to properly orient the uridine within the active site for cleavage. Our findings show that Nsp15 is a distinctive endoribonuclease that can cleave both ss- and dsRNA effectively.
MeSH term(s)	COVID-19 ; Endoribonucleases/metabolism ; Humans ; RNA, Double-Stranded/genetics ; SARS-CoV-2/genetics ; Uridine ; Viral Nonstructural Proteins/metabolism
Chemical Substances	RNA, Double-Stranded ; Viral Nonstructural Proteins ; Endoribonucleases (EC 3.1.-) ; Uridine (WHI7HQ7H85)
Language	English
Publishing date	2022-07-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkac589
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Article: Flipped Over U: Structural Basis for dsRNA Cleavage by the SARS-CoV-2 Endoribonuclease.

Frazier, Meredith N / Wilson, Isha M / Krahn, Juno M / Butay, Kevin John / Dillard, Lucas B / Borgnia, Mario J / Stanley, Robin E

bioRxiv : the preprint server for biology

2022

Abstract	Coronaviruses generate double-stranded (ds) RNA intermediates during viral replication that can activate host immune sensors. To evade activation of the host pattern recognition receptor MDA5, coronaviruses employ Nsp15, which is uridine-specific endoribonuclease. Nsp15 is proposed to associate with the coronavirus replication-transcription complex within double-membrane vesicles to cleave these dsRNA intermediates. How Nsp15 recognizes and processes dsRNA is poorly understood because previous structural studies of Nsp15 have been limited to small single-stranded (ss) RNA substrates. Here we present cryo-EM structures of SARS-CoV-2 Nsp15 bound to a 52nt dsRNA. We observed that the Nsp15 hexamer forms a platform for engaging dsRNA across multiple protomers. The structures, along with site-directed mutagenesis and RNA cleavage assays revealed critical insight into dsRNA recognition and processing. To process dsRNA Nsp15 utilizes a base-flipping mechanism to properly orient the uridine within the active site for cleavage. Our findings show that Nsp15 is a distinctive endoribonuclease that can cleave both ss- and dsRNA effectively.
Language	English
Publishing date	2022-03-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.03.02.480688
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