Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors[S]

NPPM binding interactions is based on computational docking and rational loss-of-function approaches. While those approaches have been informative, we still lack an adequate understanding of the basis for the high selectivity of NPPMs among closely related Sec14-like PITPs. Herein, we describe a Sec...
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Gespeichert in:

Autor*in:	Danish Khan [verfasserIn] Kaitlyn R. McGrath [verfasserIn] Oleksandra Dorosheva [verfasserIn] Vytas A. Bankaitis [verfasserIn] Ashutosh Tripathi [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2016

Schlagwörter:	lipid signaling lipid transfer proteins phospholipids phosphatidylinositol transfer protein phosphatidylcholine phosphoinositides

Übergeordnetes Werk:	In: Journal of Lipid Research - Elsevier, 2021, 57(2016), 4, Seite 650-662
Übergeordnetes Werk:	volume:57 ; year:2016 ; number:4 ; pages:650-662

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1194/jlr.M066381

Katalog-ID:	DOAJ000887005

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allfields	10.1194/jlr.M066381 doi (DE-627)DOAJ000887005 (DE-599)DOAJeb7182128aa3442a847fbcd9ce723434 DE-627 ger DE-627 rakwb eng QD415-436 Danish Khan verfasserin aut Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors[S] 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Sec14-like phosphatidylinositol transfer proteins (PITPs) play important biological functions in integrating multiple aspects of intracellular lipid metabolism with phosphatidylinositol-4-phosphate signaling. As such, these proteins offer new opportunities for highly selective chemical interference with specific phosphoinositide pathways in cells. The first and best characterized small molecule inhibitors of the yeast PITP, Sec14, are nitrophenyl(4-(2-methoxyphenyl)piperazin-1-yl)methanones (NPPMs), and a hallmark feature of NPPMs is their exquisite targeting specificities for Sec14 relative to other closely related Sec14-like PITPs. Our present understanding of Sec14::NPPM binding interactions is based on computational docking and rational loss-of-function approaches. While those approaches have been informative, we still lack an adequate understanding of the basis for the high selectivity of NPPMs among closely related Sec14-like PITPs. Herein, we describe a Sec14 motif, which we term the VV signature, that contributes significantly to the NPPM sensitivity/resistance of Sec14-like phosphatidylinositol (PtdIns)/phosphatidylcholine (PtdCho) transfer proteins. The data not only reveal previously unappreciated determinants that govern Sec14-like PITP sensitivities to NPPMs, but enable predictions of which Sec14-like PtdIns/PtdCho transfer proteins are likely to be NPPM resistant or sensitive based on primary sequence considerations. Finally, the data provide independent evidence in support of previous studies highlighting the importance of Sec14 residue Ser173 in the mechanism by which NPPMs engage and inhibit Sec14-like PITPs. lipid signaling lipid transfer proteins phospholipids phosphatidylinositol transfer protein phosphatidylcholine phosphoinositides Biochemistry Kaitlyn R. McGrath verfasserin aut Oleksandra Dorosheva verfasserin aut Vytas A. Bankaitis verfasserin aut Ashutosh Tripathi verfasserin aut In Journal of Lipid Research Elsevier, 2021 57(2016), 4, Seite 650-662 (DE-627)26601593X (DE-600)1466675-3 15397262 nnns volume:57 year:2016 number:4 pages:650-662 https://doi.org/10.1194/jlr.M066381 kostenfrei https://doaj.org/article/eb7182128aa3442a847fbcd9ce723434 kostenfrei http://www.sciencedirect.com/science/article/pii/S0022227520354201 kostenfrei https://doaj.org/toc/0022-2275 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2006 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 57 2016 4 650-662
spelling	10.1194/jlr.M066381 doi (DE-627)DOAJ000887005 (DE-599)DOAJeb7182128aa3442a847fbcd9ce723434 DE-627 ger DE-627 rakwb eng QD415-436 Danish Khan verfasserin aut Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors[S] 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Sec14-like phosphatidylinositol transfer proteins (PITPs) play important biological functions in integrating multiple aspects of intracellular lipid metabolism with phosphatidylinositol-4-phosphate signaling. As such, these proteins offer new opportunities for highly selective chemical interference with specific phosphoinositide pathways in cells. The first and best characterized small molecule inhibitors of the yeast PITP, Sec14, are nitrophenyl(4-(2-methoxyphenyl)piperazin-1-yl)methanones (NPPMs), and a hallmark feature of NPPMs is their exquisite targeting specificities for Sec14 relative to other closely related Sec14-like PITPs. Our present understanding of Sec14::NPPM binding interactions is based on computational docking and rational loss-of-function approaches. While those approaches have been informative, we still lack an adequate understanding of the basis for the high selectivity of NPPMs among closely related Sec14-like PITPs. Herein, we describe a Sec14 motif, which we term the VV signature, that contributes significantly to the NPPM sensitivity/resistance of Sec14-like phosphatidylinositol (PtdIns)/phosphatidylcholine (PtdCho) transfer proteins. The data not only reveal previously unappreciated determinants that govern Sec14-like PITP sensitivities to NPPMs, but enable predictions of which Sec14-like PtdIns/PtdCho transfer proteins are likely to be NPPM resistant or sensitive based on primary sequence considerations. Finally, the data provide independent evidence in support of previous studies highlighting the importance of Sec14 residue Ser173 in the mechanism by which NPPMs engage and inhibit Sec14-like PITPs. lipid signaling lipid transfer proteins phospholipids phosphatidylinositol transfer protein phosphatidylcholine phosphoinositides Biochemistry Kaitlyn R. McGrath verfasserin aut Oleksandra Dorosheva verfasserin aut Vytas A. Bankaitis verfasserin aut Ashutosh Tripathi verfasserin aut In Journal of Lipid Research Elsevier, 2021 57(2016), 4, Seite 650-662 (DE-627)26601593X (DE-600)1466675-3 15397262 nnns volume:57 year:2016 number:4 pages:650-662 https://doi.org/10.1194/jlr.M066381 kostenfrei https://doaj.org/article/eb7182128aa3442a847fbcd9ce723434 kostenfrei http://www.sciencedirect.com/science/article/pii/S0022227520354201 kostenfrei https://doaj.org/toc/0022-2275 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2006 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 57 2016 4 650-662
allfields_unstemmed	10.1194/jlr.M066381 doi (DE-627)DOAJ000887005 (DE-599)DOAJeb7182128aa3442a847fbcd9ce723434 DE-627 ger DE-627 rakwb eng QD415-436 Danish Khan verfasserin aut Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors[S] 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Sec14-like phosphatidylinositol transfer proteins (PITPs) play important biological functions in integrating multiple aspects of intracellular lipid metabolism with phosphatidylinositol-4-phosphate signaling. As such, these proteins offer new opportunities for highly selective chemical interference with specific phosphoinositide pathways in cells. The first and best characterized small molecule inhibitors of the yeast PITP, Sec14, are nitrophenyl(4-(2-methoxyphenyl)piperazin-1-yl)methanones (NPPMs), and a hallmark feature of NPPMs is their exquisite targeting specificities for Sec14 relative to other closely related Sec14-like PITPs. Our present understanding of Sec14::NPPM binding interactions is based on computational docking and rational loss-of-function approaches. While those approaches have been informative, we still lack an adequate understanding of the basis for the high selectivity of NPPMs among closely related Sec14-like PITPs. Herein, we describe a Sec14 motif, which we term the VV signature, that contributes significantly to the NPPM sensitivity/resistance of Sec14-like phosphatidylinositol (PtdIns)/phosphatidylcholine (PtdCho) transfer proteins. The data not only reveal previously unappreciated determinants that govern Sec14-like PITP sensitivities to NPPMs, but enable predictions of which Sec14-like PtdIns/PtdCho transfer proteins are likely to be NPPM resistant or sensitive based on primary sequence considerations. Finally, the data provide independent evidence in support of previous studies highlighting the importance of Sec14 residue Ser173 in the mechanism by which NPPMs engage and inhibit Sec14-like PITPs. lipid signaling lipid transfer proteins phospholipids phosphatidylinositol transfer protein phosphatidylcholine phosphoinositides Biochemistry Kaitlyn R. McGrath verfasserin aut Oleksandra Dorosheva verfasserin aut Vytas A. Bankaitis verfasserin aut Ashutosh Tripathi verfasserin aut In Journal of Lipid Research Elsevier, 2021 57(2016), 4, Seite 650-662 (DE-627)26601593X (DE-600)1466675-3 15397262 nnns volume:57 year:2016 number:4 pages:650-662 https://doi.org/10.1194/jlr.M066381 kostenfrei https://doaj.org/article/eb7182128aa3442a847fbcd9ce723434 kostenfrei http://www.sciencedirect.com/science/article/pii/S0022227520354201 kostenfrei https://doaj.org/toc/0022-2275 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2006 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 57 2016 4 650-662
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allfieldsSound	10.1194/jlr.M066381 doi (DE-627)DOAJ000887005 (DE-599)DOAJeb7182128aa3442a847fbcd9ce723434 DE-627 ger DE-627 rakwb eng QD415-436 Danish Khan verfasserin aut Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors[S] 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Sec14-like phosphatidylinositol transfer proteins (PITPs) play important biological functions in integrating multiple aspects of intracellular lipid metabolism with phosphatidylinositol-4-phosphate signaling. As such, these proteins offer new opportunities for highly selective chemical interference with specific phosphoinositide pathways in cells. The first and best characterized small molecule inhibitors of the yeast PITP, Sec14, are nitrophenyl(4-(2-methoxyphenyl)piperazin-1-yl)methanones (NPPMs), and a hallmark feature of NPPMs is their exquisite targeting specificities for Sec14 relative to other closely related Sec14-like PITPs. Our present understanding of Sec14::NPPM binding interactions is based on computational docking and rational loss-of-function approaches. While those approaches have been informative, we still lack an adequate understanding of the basis for the high selectivity of NPPMs among closely related Sec14-like PITPs. Herein, we describe a Sec14 motif, which we term the VV signature, that contributes significantly to the NPPM sensitivity/resistance of Sec14-like phosphatidylinositol (PtdIns)/phosphatidylcholine (PtdCho) transfer proteins. The data not only reveal previously unappreciated determinants that govern Sec14-like PITP sensitivities to NPPMs, but enable predictions of which Sec14-like PtdIns/PtdCho transfer proteins are likely to be NPPM resistant or sensitive based on primary sequence considerations. Finally, the data provide independent evidence in support of previous studies highlighting the importance of Sec14 residue Ser173 in the mechanism by which NPPMs engage and inhibit Sec14-like PITPs. lipid signaling lipid transfer proteins phospholipids phosphatidylinositol transfer protein phosphatidylcholine phosphoinositides Biochemistry Kaitlyn R. McGrath verfasserin aut Oleksandra Dorosheva verfasserin aut Vytas A. Bankaitis verfasserin aut Ashutosh Tripathi verfasserin aut In Journal of Lipid Research Elsevier, 2021 57(2016), 4, Seite 650-662 (DE-627)26601593X (DE-600)1466675-3 15397262 nnns volume:57 year:2016 number:4 pages:650-662 https://doi.org/10.1194/jlr.M066381 kostenfrei https://doaj.org/article/eb7182128aa3442a847fbcd9ce723434 kostenfrei http://www.sciencedirect.com/science/article/pii/S0022227520354201 kostenfrei https://doaj.org/toc/0022-2275 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2006 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 57 2016 4 650-662
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source	In Journal of Lipid Research 57(2016), 4, Seite 650-662 volume:57 year:2016 number:4 pages:650-662
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authorswithroles_txt_mv	Danish Khan @@aut@@ Kaitlyn R. McGrath @@aut@@ Oleksandra Dorosheva @@aut@@ Vytas A. Bankaitis @@aut@@ Ashutosh Tripathi @@aut@@
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callnumber-first	Q - Science
author	Danish Khan
spellingShingle	Danish Khan misc QD415-436 misc lipid signaling misc lipid transfer proteins misc phospholipids misc phosphatidylinositol transfer protein misc phosphatidylcholine misc phosphoinositides misc Biochemistry Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors[S]
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topic_title	QD415-436 Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors[S] lipid signaling lipid transfer proteins phospholipids phosphatidylinositol transfer protein phosphatidylcholine phosphoinositides
topic	misc QD415-436 misc lipid signaling misc lipid transfer proteins misc phospholipids misc phosphatidylinositol transfer protein misc phosphatidylcholine misc phosphoinositides misc Biochemistry
topic_unstemmed	misc QD415-436 misc lipid signaling misc lipid transfer proteins misc phospholipids misc phosphatidylinositol transfer protein misc phosphatidylcholine misc phosphoinositides misc Biochemistry
topic_browse	misc QD415-436 misc lipid signaling misc lipid transfer proteins misc phospholipids misc phosphatidylinositol transfer protein misc phosphatidylcholine misc phosphoinositides misc Biochemistry
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title	Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors[S]
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title_full	Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors[S]
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author_browse	Danish Khan Kaitlyn R. McGrath Oleksandra Dorosheva Vytas A. Bankaitis Ashutosh Tripathi
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title_sort	structural elements that govern sec14-like pitp sensitivities to potent small molecule inhibitors[s]
callnumber	QD415-436
title_auth	Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors[S]
abstract	Sec14-like phosphatidylinositol transfer proteins (PITPs) play important biological functions in integrating multiple aspects of intracellular lipid metabolism with phosphatidylinositol-4-phosphate signaling. As such, these proteins offer new opportunities for highly selective chemical interference with specific phosphoinositide pathways in cells. The first and best characterized small molecule inhibitors of the yeast PITP, Sec14, are nitrophenyl(4-(2-methoxyphenyl)piperazin-1-yl)methanones (NPPMs), and a hallmark feature of NPPMs is their exquisite targeting specificities for Sec14 relative to other closely related Sec14-like PITPs. Our present understanding of Sec14::NPPM binding interactions is based on computational docking and rational loss-of-function approaches. While those approaches have been informative, we still lack an adequate understanding of the basis for the high selectivity of NPPMs among closely related Sec14-like PITPs. Herein, we describe a Sec14 motif, which we term the VV signature, that contributes significantly to the NPPM sensitivity/resistance of Sec14-like phosphatidylinositol (PtdIns)/phosphatidylcholine (PtdCho) transfer proteins. The data not only reveal previously unappreciated determinants that govern Sec14-like PITP sensitivities to NPPMs, but enable predictions of which Sec14-like PtdIns/PtdCho transfer proteins are likely to be NPPM resistant or sensitive based on primary sequence considerations. Finally, the data provide independent evidence in support of previous studies highlighting the importance of Sec14 residue Ser173 in the mechanism by which NPPMs engage and inhibit Sec14-like PITPs.
abstractGer	Sec14-like phosphatidylinositol transfer proteins (PITPs) play important biological functions in integrating multiple aspects of intracellular lipid metabolism with phosphatidylinositol-4-phosphate signaling. As such, these proteins offer new opportunities for highly selective chemical interference with specific phosphoinositide pathways in cells. The first and best characterized small molecule inhibitors of the yeast PITP, Sec14, are nitrophenyl(4-(2-methoxyphenyl)piperazin-1-yl)methanones (NPPMs), and a hallmark feature of NPPMs is their exquisite targeting specificities for Sec14 relative to other closely related Sec14-like PITPs. Our present understanding of Sec14::NPPM binding interactions is based on computational docking and rational loss-of-function approaches. While those approaches have been informative, we still lack an adequate understanding of the basis for the high selectivity of NPPMs among closely related Sec14-like PITPs. Herein, we describe a Sec14 motif, which we term the VV signature, that contributes significantly to the NPPM sensitivity/resistance of Sec14-like phosphatidylinositol (PtdIns)/phosphatidylcholine (PtdCho) transfer proteins. The data not only reveal previously unappreciated determinants that govern Sec14-like PITP sensitivities to NPPMs, but enable predictions of which Sec14-like PtdIns/PtdCho transfer proteins are likely to be NPPM resistant or sensitive based on primary sequence considerations. Finally, the data provide independent evidence in support of previous studies highlighting the importance of Sec14 residue Ser173 in the mechanism by which NPPMs engage and inhibit Sec14-like PITPs.
abstract_unstemmed	Sec14-like phosphatidylinositol transfer proteins (PITPs) play important biological functions in integrating multiple aspects of intracellular lipid metabolism with phosphatidylinositol-4-phosphate signaling. As such, these proteins offer new opportunities for highly selective chemical interference with specific phosphoinositide pathways in cells. The first and best characterized small molecule inhibitors of the yeast PITP, Sec14, are nitrophenyl(4-(2-methoxyphenyl)piperazin-1-yl)methanones (NPPMs), and a hallmark feature of NPPMs is their exquisite targeting specificities for Sec14 relative to other closely related Sec14-like PITPs. Our present understanding of Sec14::NPPM binding interactions is based on computational docking and rational loss-of-function approaches. While those approaches have been informative, we still lack an adequate understanding of the basis for the high selectivity of NPPMs among closely related Sec14-like PITPs. Herein, we describe a Sec14 motif, which we term the VV signature, that contributes significantly to the NPPM sensitivity/resistance of Sec14-like phosphatidylinositol (PtdIns)/phosphatidylcholine (PtdCho) transfer proteins. The data not only reveal previously unappreciated determinants that govern Sec14-like PITP sensitivities to NPPMs, but enable predictions of which Sec14-like PtdIns/PtdCho transfer proteins are likely to be NPPM resistant or sensitive based on primary sequence considerations. Finally, the data provide independent evidence in support of previous studies highlighting the importance of Sec14 residue Ser173 in the mechanism by which NPPMs engage and inhibit Sec14-like PITPs.
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title_short	Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors[S]
url	https://doi.org/10.1194/jlr.M066381 https://doaj.org/article/eb7182128aa3442a847fbcd9ce723434 http://www.sciencedirect.com/science/article/pii/S0022227520354201 https://doaj.org/toc/0022-2275
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up_date	2024-07-03T17:06:31.997Z
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Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors[S]

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