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Article ; Online: Room-temperature crystallography reveals altered binding of small-molecule fragments to PTP1B.

Skaist Mehlman, Tamar / Biel, Justin T / Azeem, Syeda Maryam / Nelson, Elliot R / Hossain, Sakib / Dunnett, Louise / Paterson, Neil G / Douangamath, Alice / Talon, Romain / Axford, Danny / Orins, Helen / von Delft, Frank / Keedy, Daniel A

eLife

2023 Volume 12

Abstract: Much of our current understanding of how small-molecule ligands interact with proteins stems from X-ray crystal structures determined at cryogenic (cryo) temperature. For proteins alone, room-temperature (RT) crystallography can reveal previously hidden, ...

Abstract	Much of our current understanding of how small-molecule ligands interact with proteins stems from X-ray crystal structures determined at cryogenic (cryo) temperature. For proteins alone, room-temperature (RT) crystallography can reveal previously hidden, biologically relevant alternate conformations. However, less is understood about how RT crystallography may impact the conformational landscapes of protein-ligand complexes. Previously, we showed that small-molecule fragments cluster in putative allosteric sites using a cryo crystallographic screen of the therapeutic target PTP1B (Keedy et al., 2018). Here, we have performed two RT crystallographic screens of PTP1B using many of the same fragments, representing the largest RT crystallographic screens of a diverse library of ligands to date, and enabling a direct interrogation of the effect of data collection temperature on protein-ligand interactions. We show that at RT, fewer ligands bind, and often more weakly - but with a variety of temperature-dependent differences, including unique binding poses, changes in solvation, new binding sites, and distinct protein allosteric conformational responses. Overall, this work suggests that the vast body of existing cryo-temperature protein-ligand structures may provide an incomplete picture, and highlights the potential of RT crystallography to help complete this picture by revealing distinct conformational modes of protein-ligand systems. Our results may inspire future use of RT crystallography to interrogate the roles of protein-ligand conformational ensembles in biological function.
MeSH term(s)	Allosteric Site ; Binding Sites ; Crystallography ; Ligands ; Temperature ; Protein Tyrosine Phosphatase, Non-Receptor Type 1/chemistry
Chemical Substances	Ligands ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 (EC 3.1.3.48)
Language	English
Publishing date	2023-03-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.84632
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Discovery of novel druggable pockets on polyomavirus VP1 through crystallographic fragment-based screening to develop capsid assembly inhibitors.

Osipov, Evgenii M / Munawar, Ali H / Beelen, Steven / Fearon, Daren / Douangamath, Alice / Wild, Conor / Weeks, Stephen D / Van Aerschot, Arthur / von Delft, Frank / Strelkov, Sergei V

RSC chemical biology

2022 Volume 3, Issue 8, Page(s) 1013–1027

Abstract: Polyomaviruses are a family of ubiquitous double-stranded DNA viruses many of which are human pathogens. These include BK polyomavirus which causes severe urinary tract infection in immunocompromised patients and Merkel cell polyomavirus associated with ... ...

Abstract	Polyomaviruses are a family of ubiquitous double-stranded DNA viruses many of which are human pathogens. These include BK polyomavirus which causes severe urinary tract infection in immunocompromised patients and Merkel cell polyomavirus associated with aggressive cancers. The small genome of polyomaviruses lacks conventional drug targets, and no specific drugs are available at present. Here we focus on the main structural protein VP1 of BK polyomavirus which is responsible for icosahedral capsid formation. To provide a foundation towards rational drug design, we crystallized truncated VP1 pentamers and subjected them to a high-throughput screening for binding drug-like fragments through a direct X-ray analysis. To enable a highly performant screening, rigorous optimization of the crystallographic pipeline and processing with the latest generation PanDDA2 software were necessary. As a result, a total of 144 binding hits were established. Importantly, the hits are well clustered in six surface pockets. Three pockets are located on the outside of the pentamer and map on the regions where the 'invading' C-terminal arm of another pentamer is attached upon capsid assembly. Another set of three pockets is situated within the wide pore along the five-fold axis of the VP1 pentamer. These pockets are situated at the interaction interface with the minor capsid protein VP2 which is indispensable for normal functioning of the virus. Here we systematically analyse the three outside pockets which are highly conserved across various polyomaviruses, while point mutations in these pockets are detrimental for viral replication. We show that one of the pockets can accommodate antipsychotic drug trifluoperazine. For each pocket, we derive pharmacophore features which enable the design of small molecules preventing the interaction between VP1 pentamers and therefore inhibiting capsid assembly. Our data lay a foundation towards a rational development of first-in-class drugs targeting polyomavirus capsid.
Language	English
Publishing date	2022-04-29
Publishing country	England
Document type	Journal Article
ISSN	2633-0679
ISSN (online)	2633-0679
DOI	10.1039/d2cb00052k
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Article ; Online: Room-temperature crystallography reveals altered binding of small-molecule fragments to PTP1B

Tamar Skaist Mehlman / Justin T Biel / Syeda Maryam Azeem / Elliot R Nelson / Sakib Hossain / Louise Dunnett / Neil G Paterson / Alice Douangamath / Romain Talon / Danny Axford / Helen Orins / Frank von Delft / Daniel A Keedy

eLife, Vol

2023 Volume 12

Abstract	Much of our current understanding of how small-molecule ligands interact with proteins stems from X-ray crystal structures determined at cryogenic (cryo) temperature. For proteins alone, room-temperature (RT) crystallography can reveal previously hidden, biologically relevant alternate conformations. However, less is understood about how RT crystallography may impact the conformational landscapes of protein-ligand complexes. Previously, we showed that small-molecule fragments cluster in putative allosteric sites using a cryo crystallographic screen of the therapeutic target PTP1B (Keedy et al., 2018). Here, we have performed two RT crystallographic screens of PTP1B using many of the same fragments, representing the largest RT crystallographic screens of a diverse library of ligands to date, and enabling a direct interrogation of the effect of data collection temperature on protein-ligand interactions. We show that at RT, fewer ligands bind, and often more weakly – but with a variety of temperature-dependent differences, including unique binding poses, changes in solvation, new binding sites, and distinct protein allosteric conformational responses. Overall, this work suggests that the vast body of existing cryo-temperature protein-ligand structures may provide an incomplete picture, and highlights the potential of RT crystallography to help complete this picture by revealing distinct conformational modes of protein-ligand systems. Our results may inspire future use of RT crystallography to interrogate the roles of protein-ligand conformational ensembles in biological function.
Keywords	ligands ; X-ray crystallography ; protein structure ; allostery ; fragment screening ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	500 ; 612
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
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Article ; Online: Allosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease.

Godoy, Andre Schutzer / Nakamura, Aline Minalli / Douangamath, Alice / Song, Yun / Noske, Gabriela Dias / Gawriljuk, Victor Oliveira / Fernandes, Rafaela Sachetto / Pereira, Humberto D Muniz / Oliveira, Ketllyn Irene Zagato / Fearon, Daren / Dias, Alexandre / Krojer, Tobias / Fairhead, Michael / Powell, Alisa / Dunnet, Louise / Brandao-Neto, Jose / Skyner, Rachael / Chalk, Rod / Bajusz, Dávid /

Bege, Miklós / Borbás, Anikó / Keserű, György Miklós / von Delft, Frank / Oliva, Glaucius

Nucleic acids research

2023 Volume 51, Issue 10, Page(s) 5255–5270

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The NSP15 endoribonuclease enzyme, known as NendoU, is highly conserved and plays a critical role in the ability of the virus to ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The NSP15 endoribonuclease enzyme, known as NendoU, is highly conserved and plays a critical role in the ability of the virus to evade the immune system. NendoU is a promising target for the development of new antiviral drugs. However, the complexity of the enzyme's structure and kinetics, along with the broad range of recognition sequences and lack of structural complexes, hampers the development of inhibitors. Here, we performed enzymatic characterization of NendoU in its monomeric and hexameric form, showing that hexamers are allosteric enzymes with a positive cooperative index, and with no influence of manganese on enzymatic activity. Through combining cryo-electron microscopy at different pHs, X-ray crystallography and biochemical and structural analysis, we showed that NendoU can shift between open and closed forms, which probably correspond to active and inactive states, respectively. We also explored the possibility of NendoU assembling into larger supramolecular structures and proposed a mechanism for allosteric regulation. In addition, we conducted a large fragment screening campaign against NendoU and identified several new allosteric sites that could be targeted for the development of new inhibitors. Overall, our findings provide insights into the complex structure and function of NendoU and offer new opportunities for the development of inhibitors.
MeSH term(s)	Humans ; Allosteric Regulation ; Amino Acid Sequence ; COVID-19 ; Cryoelectron Microscopy ; Endoribonucleases/metabolism ; SARS-CoV-2/metabolism ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/chemistry
Chemical Substances	Endoribonucleases (EC 3.1.-) ; Viral Nonstructural Proteins ; nidoviral uridylate-specific endoribonuclease (EC 3.1.-)
Language	English
Publishing date	2023-04-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
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/gkad314
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Article ; Online: Structure, mechanism and crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase.

Newman, Joseph A / Douangamath, Alice / Yadzani, Setayesh / Yosaatmadja, Yuliana / Aimon, Antony / Brandão-Neto, José / Dunnett, Louise / Gorrie-Stone, Tyler / Skyner, Rachael / Fearon, Daren / Schapira, Matthieu / von Delft, Frank / Gileadi, Opher

Nature communications

2021 Volume 12, Issue 1, Page(s) 4848

Abstract: There is currently a lack of effective drugs to treat people infected with SARS-CoV-2, the cause of the global COVID-19 pandemic. The SARS-CoV-2 Non-structural protein 13 (NSP13) has been identified as a target for anti-virals due to its high sequence ... ...

Abstract	There is currently a lack of effective drugs to treat people infected with SARS-CoV-2, the cause of the global COVID-19 pandemic. The SARS-CoV-2 Non-structural protein 13 (NSP13) has been identified as a target for anti-virals due to its high sequence conservation and essential role in viral replication. Structural analysis reveals two "druggable" pockets on NSP13 that are among the most conserved sites in the entire SARS-CoV-2 proteome. Here we present crystal structures of SARS-CoV-2 NSP13 solved in the APO form and in the presence of both phosphate and a non-hydrolysable ATP analog. Comparisons of these structures reveal details of conformational changes that provide insights into the helicase mechanism and possible modes of inhibition. To identify starting points for drug development we have performed a crystallographic fragment screen against NSP13. The screen reveals 65 fragment hits across 52 datasets opening the way to structure guided development of novel antiviral agents.
MeSH term(s)	Adenosine Triphosphate/chemistry ; Adenosine Triphosphate/metabolism ; Amino Acid Sequence ; Apoenzymes/chemistry ; Apoenzymes/metabolism ; Binding Sites ; Crystallography, X-Ray ; Drug Design ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Methyltransferases/antagonists & inhibitors ; Methyltransferases/chemistry ; Methyltransferases/metabolism ; Models, Molecular ; Phosphates/chemistry ; Phosphates/metabolism ; Protein Conformation ; RNA Helicases/antagonists & inhibitors ; RNA Helicases/chemistry ; RNA Helicases/metabolism ; RNA, Viral/chemistry ; RNA, Viral/metabolism ; SARS-CoV-2/chemistry ; SARS-CoV-2/enzymology ; Structure-Activity Relationship ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Apoenzymes ; Enzyme Inhibitors ; Phosphates ; RNA, Viral ; Viral Nonstructural Proteins ; Adenosine Triphosphate (8L70Q75FXE) ; Methyltransferases (EC 2.1.1.-) ; Nsp13 protein, SARS-CoV (EC 2.1.1.-) ; RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2021-08-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-25166-6
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Article ; Online: Crystal structure of the catalytic D2 domain of the AAA+ ATPase p97 reveals a putative helical split-washer-type mechanism for substrate unfolding.

Stach, Lasse / Morgan, Rhodri Marc / Makhlouf, Linda / Douangamath, Alice / von Delft, Frank / Zhang, Xiaodong / Freemont, Paul S

FEBS letters

2019 Volume 594, Issue 5, Page(s) 933–943

Abstract: Several pathologies have been associated with the AAA+ ATPase p97, an enzyme essential to protein homeostasis. Heterozygous polymorphisms in p97 have been shown to cause neurological disease, while elevated proteotoxic stress in tumours has made p97 an ... ...

Abstract	Several pathologies have been associated with the AAA+ ATPase p97, an enzyme essential to protein homeostasis. Heterozygous polymorphisms in p97 have been shown to cause neurological disease, while elevated proteotoxic stress in tumours has made p97 an attractive cancer chemotherapy target. The cellular processes reliant on p97 are well described. High-resolution structural models of its catalytic D2 domain, however, have proved elusive, as has the mechanism by which p97 converts the energy from ATP hydrolysis into mechanical force to unfold protein substrates. Here, we describe the high-resolution structure of the p97 D2 ATPase domain. This crystal system constitutes a valuable tool for p97 inhibitor development and identifies a potentially druggable pocket in the D2 domain. In addition, its P6
MeSH term(s)	Catalytic Domain ; Crystallography, X-Ray ; Humans ; Models, Molecular ; Mutation ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Domains ; Valosin Containing Protein/chemistry ; Valosin Containing Protein/genetics ; Valosin Containing Protein/metabolism
Chemical Substances	VCP protein, human (EC 3.6.4.6) ; Valosin Containing Protein (EC 3.6.4.6)
Language	English
Publishing date	2019-11-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.13667
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Article ; Online: In crystallo

Guo, Jingxu / Douangamath, Alice / Song, Weixiao / Coker, Alun R / Chan, A W Edith / Wood, Steve P / Cooper, Jonathan B / Resnick, Efrat / London, Nir / Delft, Frank von

Journal of structural biology: X

2020 Volume 4, Page(s) 100031

Abstract: Outbreaks of human epidemic nonbacterial gastroenteritis are mainly caused by noroviruses. Viral replication requires a 3C-like cysteine protease ( ... ...

Abstract	Outbreaks of human epidemic nonbacterial gastroenteritis are mainly caused by noroviruses. Viral replication requires a 3C-like cysteine protease (3CL
Keywords	covid19
Language	English
Publishing date	2020-07-16
Publishing country	United States
Document type	Journal Article
ISSN	2590-1524
ISSN (online)	2590-1524
DOI	10.1016/j.yjsbx.2020.100031
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Article: Crystal structure of the catalytic D2 domain of the AAA+ ATPase p97 reveals a putative helical split‐washer‐type mechanism for substrate unfolding

Stach, Lasse / Morgan, Rhodri Marc / Makhlouf, Linda / Douangamath, Alice / von Delft, Frank / Zhang, Xiaodong / Freemont, Paul S.

FEBS letters. 2020 Mar., v. 594, no. 5

2020

Abstract	Several pathologies have been associated with the AAA+ ATPase p97, an enzyme essential to protein homeostasis. Heterozygous polymorphisms in p97 have been shown to cause neurological disease, while elevated proteotoxic stress in tumours has made p97 an attractive cancer chemotherapy target. The cellular processes reliant on p97 are well described. High‐resolution structural models of its catalytic D2 domain, however, have proved elusive, as has the mechanism by which p97 converts the energy from ATP hydrolysis into mechanical force to unfold protein substrates. Here, we describe the high‐resolution structure of the p97 D2 ATPase domain. This crystal system constitutes a valuable tool for p97 inhibitor development and identifies a potentially druggable pocket in the D2 domain. In addition, its P6₁ symmetry suggests a mechanism for substrate unfolding by p97. DATABASE: The atomic coordinates and structure factors have been deposited in the PDB database under the accession numbers 6G2V, 6G2W, 6G2X, 6G2Y, 6G2Z and 6G30.
Keywords	adenosinetriphosphatase ; crystal structure ; databases ; drug therapy ; energy ; forces ; heterozygosity ; homeostasis ; hydrolysis ; nervous system diseases
Language	English
Dates of publication	2020-03
Size	p. 933-943.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.13667
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Article ; Online: Structure, mechanism and crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase

Joseph A. Newman / Alice Douangamath / Setayesh Yadzani / Yuliana Yosaatmadja / Antony Aimon / José Brandão-Neto / Louise Dunnett / Tyler Gorrie-stone / Rachael Skyner / Daren Fearon / Matthieu Schapira / Frank von Delft / Opher Gileadi

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 11

Abstract: The SARS-CoV-2 NSP13 helicase is essential for viral replication and of interest as a drug target. Here, the authors present the crystal structures of NSP13 in the apo form and bound to either phosphate or the non-hydrolysable ATP analog AMP-PNP and ... ...

Abstract	The SARS-CoV-2 NSP13 helicase is essential for viral replication and of interest as a drug target. Here, the authors present the crystal structures of NSP13 in the apo form and bound to either phosphate or the non-hydrolysable ATP analog AMP-PNP and discuss the helicase mechanism. They also perform a crystallographic fragment screening and identify 65 bound fragments, which could help in the design of new antiviral agents.
Keywords	Science ; Q
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Achieving a Good Crystal System for Crystallographic X-Ray Fragment Screening.

Collins, Patrick M / Douangamath, Alice / Talon, Romain / Dias, Alexandre / Brandao-Neto, Jose / Krojer, Tobias / von Delft, Frank

Methods in enzymology

2018 Volume 610, Page(s) 251–264

Abstract: The XChem facility at Diamond Light Source offers fragment screening by X-ray crystallography as a general access user program. The main advantage of X-ray crystallography as a primary fragment screen is that it yields directly the location and pose of ... ...

Abstract	The XChem facility at Diamond Light Source offers fragment screening by X-ray crystallography as a general access user program. The main advantage of X-ray crystallography as a primary fragment screen is that it yields directly the location and pose of the fragment hits, whether within pockets of interest or merely on surface sites: this is the key information for structure-based design and for enabling synthesis of follow-up molecules. Extensive streamlining of the screening experiment at XChem has engendered a very active user program that is generating large amounts of data: in 2017, 36 academic and industry groups generated 35,000 datasets of uniquely soaked crystals. It has also generated a large number of learnings concerning the main remaining bottleneck, namely, obtaining a suitable crystal system that will support a successful fragment screen. Here we discuss the practicalities of generating screen-ready crystals that have useful electron density maps, and how to ensure they will be successfully reproduced and usable at a facility outside the home lab.
MeSH term(s)	Animals ; Crystallization/methods ; Crystallography, X-Ray/methods ; Drug Discovery/methods ; Humans ; Protein Engineering/methods ; Proteins/chemistry ; Proteins/genetics
Chemical Substances	Proteins
Language	English
Publishing date	2018-10-15
Publishing country	United States
Document type	Journal Article
ISSN	1557-7988 ; 0076-6879
ISSN (online)	1557-7988
ISSN	0076-6879
DOI	10.1016/bs.mie.2018.09.027
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