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Article ; Online: Fusion transcripts: Unexploited vulnerabilities in cancer?

Neckles, Carla / Sundara Rajan, Soumya / Caplen, Natasha J

2019 Volume 11, Issue 1, Page(s) e1562

Abstract: Gene fusions are an important class of mutations in several cancer types and include genomic rearrangements that fuse regulatory or coding elements from two different genes. Analysis of the genetics of cancers harboring fusion oncogenes and the proteins ... ...

Abstract	Gene fusions are an important class of mutations in several cancer types and include genomic rearrangements that fuse regulatory or coding elements from two different genes. Analysis of the genetics of cancers harboring fusion oncogenes and the proteins they encode have enhanced cancer diagnosis and in some cases patient treatment. However, the effect of the complex structure of fusion genes on the biogenesis of the resulting chimeric transcripts they express is not well studied. There are two potential RNA-related vulnerabilities inherent to fusion-driven cancers: (a) the processing of the fusion precursor messenger RNA (pre-mRNA) to the mature mRNA and (b) the mature mRNA. In this study, we discuss the effects that the genetic organization of fusion oncogenes has on the generation of translatable mature RNAs and the diversity of fusion transcripts expressed in different cancer subtypes, which can fundamentally influence both tumorigenesis and treatment. We also discuss functional genomic approaches that can be utilized to identify proteins that mediate the processing of fusion pre-mRNAs. Furthermore, we assert that an enhanced understanding of fusion transcript biogenesis and the diversity of the chimeric RNAs present in fusion-driven cancers will increase the likelihood of successful application of RNA-based therapies in this class of tumors. This article is categorized under: RNA Processing > RNA Editing and Modification RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease.
MeSH term(s)	Humans ; Neoplasms/genetics ; RNA/genetics
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2019-08-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2634714-3
ISSN	1757-7012 ; 1757-7004
ISSN (online)	1757-7012
ISSN	1757-7004
DOI	10.1002/wrna.1562
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Article ; Online: HNRNPH1-dependent splicing of a fusion oncogene reveals a targetable RNA G-quadruplex interaction.

Neckles, Carla / Boer, Robert E / Aboreden, Nicholas / Cross, Allison M / Walker, Robert L / Kim, Bong-Hyun / Kim, Suntae / Schneekloth, John S / Caplen, Natasha J

RNA (New York, N.Y.)

2019 Volume 25, Issue 12, Page(s) 1731–1750

Abstract: The primary oncogenic event in ∼85% of Ewing sarcomas is a chromosomal translocation that generates a fusion oncogene encoding an aberrant transcription factor. The exact genomic breakpoints within the translocated genes, ...

Abstract	The primary oncogenic event in ∼85% of Ewing sarcomas is a chromosomal translocation that generates a fusion oncogene encoding an aberrant transcription factor. The exact genomic breakpoints within the translocated genes,
MeSH term(s)	G-Quadruplexes ; Heterogeneous-Nuclear Ribonucleoproteins/metabolism ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Protein Binding ; RNA Splicing ; RNA, Messenger/chemistry ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA-Binding Proteins
Chemical Substances	Heterogeneous-Nuclear Ribonucleoproteins ; Oncogene Proteins, Fusion ; RNA, Messenger ; RNA-Binding Proteins
Language	English
Publishing date	2019-09-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.072454.119
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Zs.A 4777: Show issues

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Article: A [32P]NAD+-based method to identify and quantitate long residence time enoyl-acyl carrier protein reductase inhibitors

Yu, Weixuan / Neckles, Carla / Chang, Andrew / Bommineni, Gopal Reddy / Spagnuolo, Lauren / Zhang, Zhuo / Liu, Nina / Lai, Christina / Truglio, James / Tonge, Peter J

Analytical biochemistry. 2015 Apr. 01, v. 474

2015

Abstract: The classical methods for quantifying drug–target residence time (tR) use loss or regain of enzyme activity in progress curve kinetic assays. However, such methods become imprecise at very long residence times, mitigating the use of alternative ... ...

Abstract	The classical methods for quantifying drug–target residence time (tR) use loss or regain of enzyme activity in progress curve kinetic assays. However, such methods become imprecise at very long residence times, mitigating the use of alternative strategies. Using the NAD(P)H-dependent FabI enoyl-acyl carrier protein (enoyl-ACP) reductase as a model system, we developed a Penefsky column-based method for direct measurement of tR, where the off-rate of the drug was determined with radiolabeled [adenylate-32P]NAD(P+) cofactor. In total, 23 FabI inhibitors were analyzed, and a mathematical model was used to estimate limits to the tR values of each inhibitor based on percentage drug–target complex recovery following gel filtration. In general, this method showed good agreement with the classical steady-state kinetic methods for compounds with tR values of 10 to 100min. In addition, we were able to identify seven long tR inhibitors (100–1500min) and to accurately determine their tR values. The method was then used to measure tR as a function of temperature, an analysis not previously possible using the standard kinetic approach due to decreased NAD(P)H stability at elevated temperatures. In general, a 4-fold difference in tR was observed when the temperature was increased from 25 to 37°C.
Keywords	NAD (coenzyme) ; NADP (coenzyme) ; drugs ; enzyme inhibitors ; gel chromatography ; mathematical models ; phosphorus ; radiolabeling ; radionuclides ; temperature
Language	English
Dates of publication	2015-0401
Size	p. 40-49.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1110-1
ISSN	1096-0309 ; 0003-2697
ISSN (online)	1096-0309
ISSN	0003-2697
DOI	10.1016/j.ab.2014.12.022
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Article: Rationalizing the Binding Kinetics for the Inhibition of the Burkholderia pseudomallei FabI1 Enoyl-ACP Reductase

Neckles, Carla / Bommineni Gopal R / Cummings Jason E / Daryaee Fereidoon / Davoodi Shabnam / Eltschkner Sandra / Hirschbeck Maria / Kisker Caroline / Slayden Richard A / Spagnuolo Lauren / Tonge Peter J / Yu Weixuan / Zhang Zhuo

Biochemistry. 2017 Apr. 04, v. 56, no. 13

2017

Abstract: There is growing awareness of the link between drugâtarget residence time and in vivo drug activity, and there are increasing efforts to determine the molecular factors that control the lifetime of a drugâtarget complex. Rational alterations in the ... ...

Abstract	There is growing awareness of the link between drugâtarget residence time and in vivo drug activity, and there are increasing efforts to determine the molecular factors that control the lifetime of a drugâtarget complex. Rational alterations in the drugâtarget residence time require knowledge of both the ground and transition states on the inhibition reaction coordinate, and we have determined the structureâkinetic relationship for 22 ethyl- or hexyl-substituted diphenyl ethers that are slow-binding inhibitors of bpFabI1, the enoyl-ACP reductase FabI1 from Burkholderia pseudomallei. Analysis of enzyme inhibition using a two-dimensional kinetic map demonstrates that the ethyl and hexyl diphenyl ethers fall into two distinct clusters. Modifications to the ethyl diphenyl ether B ring result in changes to both on and off rates, where residence times of up to â¼700 min (â¼11 h) are achieved by either ground state stabilization (PT444) or transition state destabilization (slower on rate) (PT404). By contrast, modifications to the hexyl diphenyl ether B ring result in residence times of 300 min (â¼5 h) through changes in only ground state stabilization (PT119). Structural analysis of nine enzyme:inhibitor complexes reveals that the variation in structureâkinetic relationships can be rationalized by structural rearrangements of bpFabI1 and subtle changes to the orientation of the inhibitor in the binding pocket. Finally, we demonstrate that three compounds with residence times on bpFabI1 from 118 min (â¼2 h) to 670 min (â¼11 h) have in vivo efficacy in an acute B. pseudomallei murine infection model using the virulent B. pseudomallei strain Bp400.
Keywords	Burkholderia pseudomallei ; diphenyl ethers ; drugs ; enoyl-(acyl-carrier-protein) reductase (NADH) ; enzyme inhibition ; mice ; models ; virulence
Language	English
Dates of publication	2017-0404
Size	p. 1865-1878.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021%2Facs.biochem.6b01048
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Article ; Online: Rationalizing the Binding Kinetics for the Inhibition of the Burkholderia pseudomallei FabI1 Enoyl-ACP Reductase.

Neckles, Carla / Eltschkner, Sandra / Cummings, Jason E / Hirschbeck, Maria / Daryaee, Fereidoon / Bommineni, Gopal R / Zhang, Zhuo / Spagnuolo, Lauren / Yu, Weixuan / Davoodi, Shabnam / Slayden, Richard A / Kisker, Caroline / Tonge, Peter J

Biochemistry

2017 Volume 56, Issue 13, Page(s) 1865–1878

Abstract: There is growing awareness of the link between drug-target residence time and in vivo drug activity, and there are increasing efforts to determine the molecular factors that control the lifetime of a drug-target complex. Rational alterations in the drug- ... ...

Abstract	There is growing awareness of the link between drug-target residence time and in vivo drug activity, and there are increasing efforts to determine the molecular factors that control the lifetime of a drug-target complex. Rational alterations in the drug-target residence time require knowledge of both the ground and transition states on the inhibition reaction coordinate, and we have determined the structure-kinetic relationship for 22 ethyl- or hexyl-substituted diphenyl ethers that are slow-binding inhibitors of bpFabI1, the enoyl-ACP reductase FabI1 from Burkholderia pseudomallei. Analysis of enzyme inhibition using a two-dimensional kinetic map demonstrates that the ethyl and hexyl diphenyl ethers fall into two distinct clusters. Modifications to the ethyl diphenyl ether B ring result in changes to both on and off rates, where residence times of up to ∼700 min (∼11 h) are achieved by either ground state stabilization (PT444) or transition state destabilization (slower on rate) (PT404). By contrast, modifications to the hexyl diphenyl ether B ring result in residence times of 300 min (∼5 h) through changes in only ground state stabilization (PT119). Structural analysis of nine enzyme:inhibitor complexes reveals that the variation in structure-kinetic relationships can be rationalized by structural rearrangements of bpFabI1 and subtle changes to the orientation of the inhibitor in the binding pocket. Finally, we demonstrate that three compounds with residence times on bpFabI1 from 118 min (∼2 h) to 670 min (∼11 h) have in vivo efficacy in an acute B. pseudomallei murine infection model using the virulent B. pseudomallei strain Bp400.
MeSH term(s)	Animals ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Binding Sites ; Burkholderia pseudomallei/drug effects ; Burkholderia pseudomallei/enzymology ; Burkholderia pseudomallei/genetics ; Burkholderia pseudomallei/growth & development ; Colony Count, Microbial ; Crystallography, X-Ray ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/antagonists & inhibitors ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/genetics ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/metabolism ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Female ; Gene Expression ; Kinetics ; Lung/drug effects ; Lung/microbiology ; Melioidosis/diet therapy ; Melioidosis/drug therapy ; Melioidosis/microbiology ; Mice ; Mice, Inbred BALB C ; Microbial Sensitivity Tests ; Molecular Dynamics Simulation ; Phenyl Ethers/chemistry ; Phenyl Ethers/pharmacology ; Protein Binding ; Protein Structure, Secondary ; Spleen/drug effects ; Spleen/microbiology ; Structure-Activity Relationship
Chemical Substances	Anti-Bacterial Agents ; Bacterial Proteins ; Enzyme Inhibitors ; Phenyl Ethers ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) (EC 1.3.1.9)
Language	English
Publishing date	2017-03-21
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.6b01048
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Article: Selectivity of Pyridone- and Diphenyl Ether-Based Inhibitors for the Yersinia pestis FabV Enoyl-ACP Reductase

Neckles, Carla / Pschibul Annica / Lai Cheng-Tsung / Hirschbeck Maria / Kuper Jochen / Davoodi Shabnam / Zou Junjie / Liu Nina / Pan Pan / Shah Sonam / Daryaee Fereidoon / Bommineni Gopal R / Lai Cristina / Simmerling Carlos / Kisker Caroline / Tonge Peter J

Biochemistry. 2016 May 31, v. 55, no. 21

2016

Abstract: The enoyl-ACP reductase (ENR) catalyzes the last reaction in the elongation cycle of the bacterial type II fatty acid biosynthesis (FAS-II) pathway. While the FabI ENR is a well-validated drug target in organisms such as Mycobacterium tuberculosis and ... ...

Abstract	The enoyl-ACP reductase (ENR) catalyzes the last reaction in the elongation cycle of the bacterial type II fatty acid biosynthesis (FAS-II) pathway. While the FabI ENR is a well-validated drug target in organisms such as Mycobacterium tuberculosis and Staphylococcus aureus, alternate ENR isoforms have been discovered in other pathogens, including the FabV enzyme that is the sole ENR in Yersinia pestis (ypFabV). Previously, we showed that the prototypical ENR inhibitor triclosan was a poor inhibitor of ypFabV and that inhibitors based on the 2-pyridone scaffold were more potent [Hirschbeck, M. (2012) Structure 20 (1), 89â100]. These studies were performed with the T276S FabV variant. In the work presented here, we describe a detailed examination of the mechanism and inhibition of wild-type ypFabV and the T276S variant. The T276S mutation significantly reduces the affinity of diphenyl ether inhibitors for ypFabV (20-fold â 100-fold). In addition, while T276S ypFabV generally displays an affinity for 2-pyridone inhibitors higher than that of the wild-type enzyme, the 4-pyridone scaffold yields compounds with similar affinity for both wild-type and T276S ypFabV. T276 is located at the N-terminus of the helical substrate-binding loop, and structural studies coupled with site-directed mutagenesis reveal that alterations in this residue modulate the size of the active site portal. Subsequently, we were able to probe the mechanism of time-dependent inhibition in this enzyme family by extending the inhibition studies to include P142W ypFabV, a mutation that results in a gain of slow-onset inhibition for the 4-pyridone PT156.
Keywords	Mycobacterium tuberculosis ; Staphylococcus aureus ; Yersinia pestis ; active sites ; biosynthesis ; biphenyl ; diphenyl ethers ; drugs ; enoyl-(acyl-carrier-protein) reductase (NADH) ; enzyme inhibition ; fatty acids ; pathogens ; site-directed mutagenesis
Language	English
Dates of publication	2016-0531
Size	p. 2992-3006.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021%2Facs.biochem.5b01301
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Article ; Online: A [(32)P]NAD(+)-based method to identify and quantitate long residence time enoyl-acyl carrier protein reductase inhibitors.

Yu, Weixuan / Neckles, Carla / Chang, Andrew / Bommineni, Gopal Reddy / Spagnuolo, Lauren / Zhang, Zhuo / Liu, Nina / Lai, Christina / Truglio, James / Tonge, Peter J

Analytical biochemistry

2015 Volume 474, Page(s) 40–49

Abstract: The classical methods for quantifying drug-target residence time (tR) use loss or regain of enzyme activity in progress curve kinetic assays. However, such methods become imprecise at very long residence times, mitigating the use of alternative ... ...

Abstract	The classical methods for quantifying drug-target residence time (tR) use loss or regain of enzyme activity in progress curve kinetic assays. However, such methods become imprecise at very long residence times, mitigating the use of alternative strategies. Using the NAD(P)H-dependent FabI enoyl-acyl carrier protein (enoyl-ACP) reductase as a model system, we developed a Penefsky column-based method for direct measurement of tR, where the off-rate of the drug was determined with radiolabeled [adenylate-(32)P]NAD(P(+)) cofactor. In total, 23 FabI inhibitors were analyzed, and a mathematical model was used to estimate limits to the tR values of each inhibitor based on percentage drug-target complex recovery following gel filtration. In general, this method showed good agreement with the classical steady-state kinetic methods for compounds with tR values of 10 to 100 min. In addition, we were able to identify seven long tR inhibitors (100-1500 min) and to accurately determine their tR values. The method was then used to measure tR as a function of temperature, an analysis not previously possible using the standard kinetic approach due to decreased NAD(P)H stability at elevated temperatures. In general, a 4-fold difference in tR was observed when the temperature was increased from 25 to 37 °C.
MeSH term(s)	Acyl Carrier Protein ; Biochemistry/methods ; Computer Simulation ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/antagonists & inhibitors ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/metabolism ; Enzyme Inhibitors/pharmacology ; Feasibility Studies ; High-Throughput Screening Assays ; Kinetics ; NAD/metabolism ; Phosphorus Radioisotopes ; Reproducibility of Results ; Temperature ; Time Factors
Chemical Substances	Acyl Carrier Protein ; Enzyme Inhibitors ; Phosphorus Radioisotopes ; NAD (0U46U6E8UK) ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) (EC 1.3.1.9)
Language	English
Publishing date	2015-02-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1110-1
ISSN	1096-0309 ; 0003-2697
ISSN (online)	1096-0309
ISSN	0003-2697
DOI	10.1016/j.ab.2014.12.022
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Article ; Online: Selectivity of Pyridone- and Diphenyl Ether-Based Inhibitors for the Yersinia pestis FabV Enoyl-ACP Reductase.

Neckles, Carla / Pschibul, Annica / Lai, Cheng-Tsung / Hirschbeck, Maria / Kuper, Jochen / Davoodi, Shabnam / Zou, Junjie / Liu, Nina / Pan, Pan / Shah, Sonam / Daryaee, Fereidoon / Bommineni, Gopal R / Lai, Cristina / Simmerling, Carlos / Kisker, Caroline / Tonge, Peter J

Biochemistry

2016 Volume 55, Issue 21, Page(s) 2992–3006

Abstract	The enoyl-ACP reductase (ENR) catalyzes the last reaction in the elongation cycle of the bacterial type II fatty acid biosynthesis (FAS-II) pathway. While the FabI ENR is a well-validated drug target in organisms such as Mycobacterium tuberculosis and Staphylococcus aureus, alternate ENR isoforms have been discovered in other pathogens, including the FabV enzyme that is the sole ENR in Yersinia pestis (ypFabV). Previously, we showed that the prototypical ENR inhibitor triclosan was a poor inhibitor of ypFabV and that inhibitors based on the 2-pyridone scaffold were more potent [Hirschbeck, M. (2012) Structure 20 (1), 89-100]. These studies were performed with the T276S FabV variant. In the work presented here, we describe a detailed examination of the mechanism and inhibition of wild-type ypFabV and the T276S variant. The T276S mutation significantly reduces the affinity of diphenyl ether inhibitors for ypFabV (20-fold → 100-fold). In addition, while T276S ypFabV generally displays an affinity for 2-pyridone inhibitors higher than that of the wild-type enzyme, the 4-pyridone scaffold yields compounds with similar affinity for both wild-type and T276S ypFabV. T276 is located at the N-terminus of the helical substrate-binding loop, and structural studies coupled with site-directed mutagenesis reveal that alterations in this residue modulate the size of the active site portal. Subsequently, we were able to probe the mechanism of time-dependent inhibition in this enzyme family by extending the inhibition studies to include P142W ypFabV, a mutation that results in a gain of slow-onset inhibition for the 4-pyridone PT156.
MeSH term(s)	Catalysis ; Catalytic Domain ; Crystallization ; Crystallography, X-Ray ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/antagonists & inhibitors ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/genetics ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/metabolism ; Enzyme Inhibitors/pharmacology ; Models, Molecular ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Mutation/genetics ; NAD/metabolism ; Phenyl Ethers/chemistry ; Protein Binding ; Protein Conformation ; Pyridones/chemistry ; Yersinia pestis/enzymology
Chemical Substances	Enzyme Inhibitors ; Phenyl Ethers ; Pyridones ; NAD (0U46U6E8UK) ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) (EC 1.3.1.9)
Language	English
Publishing date	2016-05-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.5b01301
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Article ; Online: Substituted diphenyl ethers as a novel chemotherapeutic platform against Burkholderia pseudomallei.

Cummings, Jason E / Beaupre, Adam J / Knudson, Susan E / Liu, Nina / Yu, Weixuan / Neckles, Carla / Wang, Hui / Khanna, Avinash / Bommineni, Gopal R / Trunck, Lily A / Schweizer, Herbert P / Tonge, Peter J / Slayden, Richard A

Antimicrobial agents and chemotherapy

2013 Volume 58, Issue 3, Page(s) 1646–1651

Abstract: Identification of a novel class of anti-Burkholderia compounds is key in addressing antimicrobial resistance to current therapies as well as naturally occurring resistance. The FabI enoyl-ACP reductase in Burkholderia is an underexploited target that ... ...

Abstract	Identification of a novel class of anti-Burkholderia compounds is key in addressing antimicrobial resistance to current therapies as well as naturally occurring resistance. The FabI enoyl-ACP reductase in Burkholderia is an underexploited target that presents an opportunity for development of a new class of inhibitors. A library of substituted diphenyl ethers was used to identify FabI1-specific inhibitors for assessment in Burkholderia pseudomallei ex vivo and murine efficacy models. Active FabI1 inhibitors were identified in a two-stage format consisting of percent inhibition screening and MIC determination by the broth microdilution method. Each compound was evaluated against the B. pseudomallei 1026b (efflux-proficient) and Bp400 (efflux-compromised) strains. In vitro screening identified candidate substituted diphenyl ethers that exhibited MICs of less than 1 μg/ml, and enzyme kinetic assays were used to assess potency and specificity against the FabI1 enzyme. These compounds demonstrated activity in a Burkholderia ex vivo efficacy model, and two demonstrated efficacy in an acute B. pseudomallei mouse infection model. This work establishes substituted diphenyl ethers as a suitable platform for development of novel anti-Burkholderia compounds that can be used for treatment of melioidosis.
MeSH term(s)	Animals ; Anti-Bacterial Agents/pharmacology ; Burkholderia pseudomallei/drug effects ; Burkholderia pseudomallei/enzymology ; Disease Models, Animal ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/antagonists & inhibitors ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/metabolism ; Female ; Melioidosis/drug therapy ; Mice ; Mice, Inbred BALB C ; Microbial Sensitivity Tests ; Phenyl Ethers/pharmacology ; Vero Cells/drug effects
Chemical Substances	Anti-Bacterial Agents ; Phenyl Ethers ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) (EC 1.3.1.9)
Language	English
Publishing date	2013-12-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.02296-13
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Article ; Online: Structure of the Yersinia pestis FabV enoyl-ACP reductase and its interaction with two 2-pyridone inhibitors.

Hirschbeck, Maria W / Kuper, Jochen / Lu, Hao / Liu, Nina / Neckles, Carla / Shah, Sonam / Wagner, Steffen / Sotriffer, Christoph A / Tonge, Peter J / Kisker, Caroline

Structure (London, England : 1993)

2012 Volume 20, Issue 1, Page(s) 89–100

Abstract: The recently discovered FabV enoyl-ACP reductase, which catalyzes the last step of the bacterial fatty acid biosynthesis (FAS-II) pathway, is a promising but unexploited drug target against the reemerging pathogen Yersinia pestis. The structure of Y. ... ...

Abstract	The recently discovered FabV enoyl-ACP reductase, which catalyzes the last step of the bacterial fatty acid biosynthesis (FAS-II) pathway, is a promising but unexploited drug target against the reemerging pathogen Yersinia pestis. The structure of Y. pestis FabV in complex with its cofactor reveals that the enzyme features the common architecture of the short-chain dehydrogenase reductase superfamily, but contains additional structural elements that are mostly folded around the usually flexible substrate-binding loop, thereby stabilizing it in a very tight conformation that seals the active site. The structures of FabV in complex with NADH and two newly developed 2-pyridone inhibitors provide insights for the development of new lead compounds, and suggest a mechanism by which the substrate-binding loop opens to admit the inhibitor, a motion that could also be coupled to the interaction of FabV with the acyl-carrier protein substrate.
MeSH term(s)	Amino Acid Sequence ; Catalytic Domain/genetics ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/chemistry ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/genetics ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/metabolism ; Models, Molecular ; Molecular Sequence Data ; Molecular Structure ; NAD/metabolism ; Protein Binding ; Protein Conformation ; Pyridones/antagonists & inhibitors ; Sequence Alignment ; Yersinia pestis/enzymology
Chemical Substances	Pyridones ; NAD (0U46U6E8UK) ; 2-hydroxypyridine (6770O3A2I5) ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) (EC 1.3.1.9)
Language	English
Publishing date	2012-01-14
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2011.07.019
Database	MEDical Literature Analysis and Retrieval System OnLINE

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