PSI Structural Biology Knowledgebase

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Community-Nominated Targets
July 2015
Drug Discovery: Solving the Structure of an Anti-hypertension Drug Target
July 2015
Retrospective: 7,000 Structures Closer to Understanding Biology
July 2015
Design and Evolution: Unveiling Translocator Proteins
June 2015
Signaling with DivL
May 2015
Signaling: A Platform for Opposing Functions
May 2015
Signaling: Securing Lipid-Protein Partnership
May 2015
Dynamic DnaK
March 2015
Iron-Sulfur Cluster Biosynthesis
December 2014
Mitochondrion: Flipping for UCP2
December 2014
Mitochondrion: Setting a New TRAP1
December 2014
Power in Numbers
August 2014
Quorum Sensing: A Groovy New Component
August 2014
Quorum Sensing: E. coli Gets Involved
August 2014
iTRAQing the Ubiquitinome
July 2014
Microbiome: The Dynamics of Infection
September 2013
Protein-Nucleic Acid Interaction: A Modified SAM to Modify tRNA
July 2013
Protein-Nucleic Acid Interaction: Versatile Glutamate
July 2013
PDZ Domains
April 2013
Alpha-Catenin Connections
March 2013
Cell-Cell Interaction: A FERM Connection
March 2013
Cell-Cell Interaction: Magic Structure from Microcrystals
March 2013
Cell-Cell Interaction: Modulating Self Recognition Affinity
March 2013
Bacterial Hemophores
January 2013
Archaeal Lipids
December 2012
Membrane Proteome: Capturing Multiple Conformations
December 2012
Lethal Tendencies
October 2012
Symmetry from Asymmetry
October 2012
A signal sensing switch
September 2012
Regulatory insights
September 2012
AlkB Homologs
August 2012
Budding ensemble
August 2012
Targeting Enzyme Function with Structural Genomics
July 2012
The machines behind the spindle assembly checkpoint
June 2012
Chaperone interactions
April 2012
Pilus Assembly Protein TadZ
April 2012
Revealing the Nuclear Pore Complex
March 2012
Topping off the proteasome
March 2012
Twist to open
March 2012
Disordered Proteins
February 2012
Analyzing an allergen
January 2012
Making Lipopolysaccharide
January 2012
Pulling on loose ends
January 2012
Terminal activation
December 2011
The Perils of Protein Secretion
November 2011
Bacterial Armor
October 2011
TLR4 regulation: heads or tails?
October 2011
Ribose production on demand
September 2011
Moving some metal
August 2011
Looking for lipids
July 2011
Ribofuranosyl Binding Protein
June 2011
A molecular switch for neuronal growth
May 2011
Cell wall recycler
May 2011
Added benefits
April 2011
NMR challenges current protein hydration dogma
March 2011
Nitrile Reductase QueF
March 2011
Tip formin
March 2011
Inhibiting factor
February 2011
PASK staying active
February 2011
Tryptophanyl-tRNA Synthetase
February 2011
Regulating nitrogen assimilation
January 2011
Subtle shifts
January 2011
Nitrobindin
December 2010
Function following form
October 2010
tRNA Isopentenyltransferase MiaA
August 2010
Importance of extension for integrin
June 2010
Phytochrome
April 2010
Alg13 Subunit of N-Acetylglucosamine Transferase
February 2010
Hemolysin BL
January 2010
Secretagogin
December 2009
Two-component signaling
December 2009
Network coverage
November 2009
Pseudouridine Synthase TruA
November 2009
Unusual cell division
October 2009
Toxin-antitoxin VapBC-5
September 2009
Salicylic Acid Binding Protein 2
August 2009
Proofreading RNA
July 2009
Ykul structure solves bacterial signaling puzzle
July 2009
Hda and DNA Replication
June 2009
Controlling p53
May 2009
Mitotic checkpoint control
May 2009
Ribonuclease and Ribonuclease Inhibitor
April 2009
The elusive helicase
April 2009
Aquaglyceroporin
March 2009
High-energy storage system
February 2009
A new class of bacterial E3 ubiquitination enzymes
January 2009
Poly(A) RNA recognition
January 2009
Activating BAX
December 2008
Scavenger Decapping Enzyme DcpS
November 2008
Bacteriophage Lambda cII Protein
October 2008
New metal-binding domain
October 2008
Blocking AmtB
September 2008
T-Rex
September 2008
Aspartate Dehydrogenase
August 2008
RNase T
July 2008
Chronophin
May 2008

Research Themes Cell biology

Community-Nominated Targets

SBKB [doi:10.3942/psi_sgkb/fm_2015_7]
Featured System - July 2015
Short description: The Community-Nominated Targets program has allowed PSI to collaborate with researchers on hundreds of systems of high biological significance.

One of the great successes of PSI Biology has been the ability to apply the powerful PSI pipelines for high-throughput structure determination to topics of interest in the wider structural biology research community. Through a program of community nominated targets, the PSI has helped researchers explore topics from ranging from protein design to translational medicine, determining more than 500 new macromolecular structures of high biological significance in the process. A few examples are given here, and many additional examples have been presented in past installments of the PSI Structural Biology Knowledgebase.


Decoding a DUF

Working with Stuart Kornfeld at Washington University School of Medicine, PSI researchers at JCSG have determined the structure and function of a new Domain of Unknown Function. DUF2233 is interesting because it is found in hundreds of bacterial proteins, but only one mammalian protein: a protein found in the Golgi that is involved in targeting proteins to the lysosome. The structure of a bacterial homolog of this protein, shown here from PDB entry 3ohg, revealed a deep active site, lined with amino acids that are conserved in the many homologous bacterial proteins (shown in brighter turquoise). Additional biochemical study revealed that these domains are involved in cleavage of sugar-phosphate compounds, such as the sugars involved in lysosomal targeting. A sulfate ion (shown here in bright yellow and red) was found in the structure in the site that may recognize phosphate in these compounds.

Click on the JSMol tab for an interactive JSmol

DUF2233 Domain (PDB entry 3ohg)

A sulfate is bound in the presumed active site, shown here colored by atom. Use the buttons to show the protein atoms with conserved amino acids shown in brighter turquoise, or a cartoon diagram with the domains colored differently.



Transition States to Translational Medicine

Vern L. Schramm at the Albert Einstein College of Medicine is an expert on using transition state analogues to inhibit key enzymes in the cell. PSI researchers at NYSGRC have worked with him for many years to uncover the structural details of these interactions and to use them to design new therapeutic drugs. The structure shown here, from PDB entry 4ffs, is one of their recent successes. It shows a new inhibitor (in spheres) that binds tightly to the active site of an enzyme from Helicobacter pylori, a bacterium involved in the development of stomach ulcers. The inhibitor blocks the enzyme, but is also highly specific. This is important in an ulcer-fighting drug, so that the drug will fight the pathogenic bacterium but spare the normal bacterial flora.

Click on the JSMol tab for an interactive JSmol

5'-Methylthioadenosine Nucleosidase (PDB entry 4ffs)

The inhibitor is shown with spheres and atomic colors, and a water molecule that may be important in the reaction is shown in turquoise. Notice how the active site, which surrounds the inhibitor, is composed of amino acids from both chains, colored blue and green. Use the buttons to show different representations of the protein and zoom in on the inhibitor.



Tails and Targeting

PSI researchers at NESG have joined up with Monica Roth at Robert Wood Johnson Medical School to uncover the structural basis of targeting of a retrovirus. The integrase enzyme of Maloney Murine Leukemia Virus (MLV) favors sites near active genes when it integrates its viral genome into the host genome. This is beneficial for the virus, since it ensures that the viral genome will be actively transcribed, but can cause big problems for the host, since these sites may cause oncogenic mutations. PSI researchers have determined the NMR structure of the domain of MLV integrase that is involved in this targeting, shown here from PDB entry 2m9u. It has a long, flexible tail, and NMR analysis revealed that many amino acids in this tail (shown in red), interact with chromatin proteins. This result allowed them to design a truncated integrase that may reduce tumor-promoting activity when MLV is used in human gene replacement therapy.

Click on this image for an interactive JSmol

MLV integrase C-terminal domain (PDB entry 2m9u)

This JSmol is looping through the 20 conformations determined in the NMR structure analysis. Residues colored in red showed changes in the NMR spectrum when the protein associated with the cellular protein Brd3.



References

  1. 3ohg: Das, D. et al. Structure and function of the DUF2233 domain in bacteria and in the human mannose 6-phosphate uncovering enzyme. J. Biol. Chem. 288, 16789-16799 (2013).

  2. 4ffs: Wang, S. et al. A picomolar transition state analogue inhibitor of MTAN as a specific antibiotic for Helicobacter pylori. Biochem. 51, 6892-6894 (2012).

  3. 2m9u: Aiyer, S. et al. Altering murine leukemia virus integration through disruption of the integrase and BET protein family interaction. Nucl. Acids Res. 42, 5917-5928 (2014).

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health