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Structural variation of protein-ligand complexes of the first bromodomain of BRD4

Ellen Guest, Stephen Pickett, Jonathan Hirst
2021 Organic and biomolecular chemistry  
The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) family, plays a key role in several diseases, especially cancers.  ...  With increased interest in BRD4 as...  ...  H. is supported by the Royal Academy of Engineering under the Chairs in Emerging Technologies scheme.  ... 
doi:10.1039/d1ob00658d pmid:34105560 fatcat:7rzgvh6hifenll5hdrxrxtfbd4

Architecture and hydration of the arginine-binding site of neuropilin-1

Filipa Mota, Constantina Fotinou, Rohini R. Rana, A. W. Edith Chan, Tamas Yelland, Mohamed T. Arooz, Andrew P. O'Leary, Jennie Hutton, Paul Frankel, Ian Zachary, David Selwood, Snezana Djordjevic
2018 The FEBS Journal  
We observed side chain flexibility for Tyr297 and Asp320 in the six new high-resolution crystal structures of arginine analogues bound to NRP1.  ...  Displacement of certain conserved water molecules by a ligand's functional groups may contribute to binding affinity, whilst other water molecules perform as protein-ligand bridges.  ...  Analysis of ordered water molecules The high-resolution X-ray crystal structures showed additional density consistent with water molecules in the binding site.  ... 
doi:10.1111/febs.14405 pmid:29430837 pmcid:PMC5947257 fatcat:i24nvzoghfafdpkeeazgvshxj4

Cluster analysis of consensus water sites in thrombin and trypsin shows conservation between serine proteases and contributions to ligand specificity

Paul C. Sanschagrin, Leslie A. Kuhn
1998 Protein Science  
Thus, in addition to facilitating the analysis of water sites from multiple structures, cluster analysis provides a useful tool for distinguishing between conserved features within a protein family and  ...  Cluster analysis also identified water sites conserved in thrombin but not trypsin, and vice versa, providing a list of water sites that may contribute to ligand discrimination.  ...  Acknowledgments We would like to thank Cindy Fisher (Structural Bioinformatics, Inc.) and Alexander Tulinsky (Michigan State University) for their valuable feedback on the manuscript, and also acknowledge  ... 
doi:10.1002/pro.5560071002 pmid:9792092 pmcid:PMC2143843 fatcat:m5fyvmc4dratlc2kjrmg6425xq

Crystal structure at 1.0 Å resolution of human p56lckSH2 domain in complex with a short phosphotyrosyl peptide

L. Tong, T. C. Warren, J. King, R. Betageri, J. Rose, S. Jakes
1996 Acta Crystallographica Section A Foundations of Crystallography  
COMPUTING IN MODELLING, ANALYSIS & DESIGN C-87 the chances of success in "bootstrapping" from an unpromising molecular replacement starting point to a complete structure.  ...  We will also discuss the two main concems at the moment in the fields of structure refinement and validation where Bayesian methods have much to offer. namely (l) getting better reliability indicators  ...  VII 48824, USA Protein recognition of ligands. from nucleic acids to small molecule inhibitors, is usually mediated by bound water molecules bridging the protein-ligand interface.  ... 
doi:10.1107/s0108767396095608 fatcat:gto24lolkzet3nmdhbw5kyjmlm

Interaction of serum amyloid P component with hexanoyl bis(D-proline) (CPHPC)

Simon E. Kolstoe, Michelle C. Jenvey, Alan Purvis, Mark E. Light, Darren Thompson, Peter Hughes, Mark B. Pepys, Stephen P. Wood
2014 Acta Crystallographica Section D: Biological Crystallography  
Conformational isomers of CPHPC observed in solution by HPLC and by X-ray analysis are compared with the protein-bound form.  ...  Five molecules of the bivalent ligand cross-link and stabilize pairs of SAP molecules, forming a decameric complex that is rapidly cleared from the circulation by the liver.  ...  In this paper, we revisit the details of the structural analysis of calcium-bound SAP in complex with CPHPC and present a higher resolution study enabled by crystallization of the complex with cadmium  ... 
doi:10.1107/s1399004714013455 pmid:25084341 pmcid:PMC4118831 fatcat:7cn3qfnjhnfwzgtcnkghmjtbki

Structures of PPARγ complexed with lobeglitazone and pioglitazone reveal key determinants for the recognition of antidiabetic drugs

Min A Lee, Lingchen Tan, Huiseon Yang, Yeong-Gwan Im, Young Jun Im
2017 Scientific Reports  
To identify the structural determinants for the high potency of lobeglitazone as a PPARγ agonist, we determined the crystal structures of the PPARγ ligand binding domain (LBD) in complex with lobeglitazone  ...  Comparison of ligand-bound PPARγ structures revealed that the binding modes of TZDs are well conserved.  ...  Acknowledgements This project was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (grant no.  ... 
doi:10.1038/s41598-017-17082-x pmid:29203903 pmcid:PMC5715099 fatcat:mzx752xe4nfvzdm2pna3zov5ge

A complement to the modern crystallographer's toolbox: caged gadolinium complexes with versatile binding modes

Meike Stelter, Rafael Molina, Sandra Jeudy, Richard Kahn, Chantal Abergel, Juan A. Hermoso
2014 Acta Crystallographica Section D: Biological Crystallography  
The complexes contained multidentate ligand molecules with different functional groups to provide a panel of possible interactions with the protein.  ...  A set of seven caged gadolinium complexes were used as vectors for introducing the chelated Gd3+ion into protein crystals in order to provide strong anomalous scattering forde novophasing.  ...  This work was supported by the Spanish Ministry of Economy and Competitiveness (JCI-2011-09308 to RM and BFU2011-25326 to JAH) and the Government of the Community of Madrid (S2010/BMD-2457 to JAH).  ... 
doi:10.1107/s1399004714005483 pmid:24914962 fatcat:kpabqnuekjh5fnxqy7lxfp5sha

WaterScore: a novel method for distinguishing between bound and displaceable water molecules in the crystal structure of the binding site of protein-ligand complexes

Alfonso T. García-Sosa, Ricardo L. Mancera, Philip M. Dean
2003 Journal of Molecular Modeling  
, with the probability of observing the water molecules in the same location in the crystal structure of the ligand-complexed form.  ...  We have performed a multivariate logistic regression analysis to establish a statistical correlation between the structural properties of water molecules in the binding site of a free protein crystal structure  ...  RLM is also a Research Fellow of Hughes Hall, Cambridge. We also thank Mr. Benjamin Carrington for his valuable help in the production of some of the figures, Dr.  ... 
doi:10.1007/s00894-003-0129-x pmid:12756610 fatcat:dwsrxjbzgjdkfff2k4i3qanu4e

High-throughput structures of protein–ligand complexes at room temperature using serial femtosecond crystallography

Tadeo Moreno-Chicano, Ali Ebrahim, Danny Axford, Martin V. Appleby, John H. Beale, Amanda K. Chaplin, Helen M. E. Duyvesteyn, Reza A. Ghiladi, Shigeki Owada, Darren A. Sherrell, Richard W. Strange, Hiroshi Sugimoto (+4 others)
2019 IUCrJ  
High-throughput X-ray crystal structures of proteinligand complexes are critical to pharmaceutical drug development.  ...  This efficiency in both sample and XFEL beamtime opens the door to true high-throughput screening of proteinligand complexes using SFX.  ...  We are grateful to an anonymous reviewer of the manuscript for the suggestion of generating isomorphous difference maps for the two DHP ligand-bound structures. Author contributions are as follows.  ... 
doi:10.1107/s2052252519011655 pmid:31709063 pmcid:PMC6830213 fatcat:i6siicfgbzhjnkhyfjzcaj4za4

Carbohydrate binding sites in a pancreatic α-amylase-substrate complex, derived from X-ray structure analysis at 2.1 Å resolution

Minxie Qian, Richard Haser, FranÇoise Payan
2008 Protein Science  
The crystal structure of the maltopentaose complex was refined at 2.1 A resolution, to an R-factor of 17.5%, with an RMS deviation in bond distances of 0.007 A.  ...  The model includes all 496 residues of the enzyme, 1 calcium ion, 1 chloride ion, 425 water molecules, and 3 bound sugar rings. The binding sites are characterized and described in detail.  ...  Solvent structure The final G5 complex model contains 425 ordered water molecules, instead of 353 in the free enzyme molecular model.  ... 
doi:10.1002/pro.5560040414 pmid:7613472 pmcid:PMC2143103 fatcat:xdndybqmubhwjfkvbosmv76s3e

Limitations and lessons in the use of X-ray structural information in drug design

A DAVIS, S STGALLAY, G KLEYWEGT
2008 Drug Discovery Today  
Advances in structural and molecular biology, as well as in biophysics, have led to the determination of high-resolution atomic structures of many of the protein targets of drug discovery projects.  ...  For instance, p38 kinase is a target that is well validated in the clinic with respect to its role in inflammation, and many high-resolution crystal structures are available.  ...  GK was supported by Uppsala University and the Royal Swedish Academy of Sciences during part of this work.  ... 
doi:10.1016/j.drudis.2008.06.006 pmid:18617015 pmcid:PMC7185550 fatcat:2z4arell7jcjpiukh5xwjmmkze

Predicting and analyzing determinants of water-mediated ligand recognition

L. A. Kuhn, M. L. Raymer, W. F. Punch, P. C. Sanschagrin, E. D. Goodman
1996 Acta Crystallographica Section A Foundations of Crystallography  
COMPUTING IN MODELLING, ANALYSIS & DESIGN C-87 the chances of success in "bootstrapping" from an unpromising molecular replacement starting point to a complete structure.  ...  We will also discuss the two main concems at the moment in the fields of structure refinement and validation where Bayesian methods have much to offer. namely (l) getting better reliability indicators  ...  VII 48824, USA Protein recognition of ligands. from nucleic acids to small molecule inhibitors, is usually mediated by bound water molecules bridging the protein-ligand interface.  ... 
doi:10.1107/s0108767396095621 fatcat:ox6garkgwfgpvdird46sqquuqy

High resolution crystal structures of unliganded and liganded human liver ACBP reveal a new mode of binding for the acyl-CoA ligand

Jukka P. Taskinen, Daan M. van Aalten, Jens Knudsen, Rik K. Wierenga
2006 Proteins: Structure, Function, and Bioinformatics  
Here high resolution crystal structures of human cytosolic liver ACBP, unliganded and liganded with a physiological ligand, myristoyl-CoA are described.  ...  pocket of one ACBP molecule and the acyl chain is bound in the pocket of the other ACBP molecule.  ...  The coordinates of the unliganded and liganded hL-ACBP structures have been deposited in the RCSB-PDB with entry codes 2FJ9 and 2CB8, respectively.  ... 
doi:10.1002/prot.21124 pmid:17044054 fatcat:6k6ztjgb55dp5ivtnffcbkquiy

Conformational Variability of Benzamidinium-Based Inhibitors

Xue Li, Xiao He, Bing Wang, Kenneth Merz
2009 Journal of the American Chemical Society  
However, the quality of a protein/ligand complex determined using X-ray crystallography is dependent on the size of the protein, crystal quality and the realized resolution.  ...  Determining the structure of a small molecule bound to a biological receptor (e.g., a protein implicated in a disease state) is a necessary step in structure-based drug design.  ...  Shaoliang Zheng at SUNY-Buffalo for valuable discussion in the torsion motif preferences of small crystal structures from CSD.  ... 
doi:10.1021/ja9010833 pmid:19435349 pmcid:PMC2730048 fatcat:eji2mxxqkjftrf3yalewqrtfji

Conformational changes of glucose/galactose-binding protein illuminated by open, unliganded, and ultra-high-resolution ligand-bound structures

M. Jack Borrok, Laura L. Kiessling, Katrina T. Forest
2007 Protein Science  
GGBP, like other periplasmic binding proteins, can exist in open (ligand-free) and closed (ligand-bound) states.  ...  We report a 0.92 Å resolution structure of GGBP from Escherichia coli in the glucose-bound state and the first structure of an open, unbound form of GGBP (at 1.55 Å resolution).  ...  This study made use of the National Magnetic Resonance Facility at Madison, which is supported by NIH grants P41RR02301 (BRTP/NCRR) and P41GM66326 (NIGMS).  ... 
doi:10.1110/ps.062707807 pmid:17473016 pmcid:PMC2206672 fatcat:k3e77eq2rrhrjltdaebeikdt6i
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