PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons

Related Articles
Design and Evolution: Molecular Sleuthing Reveals Drug Selectivity
June 2015
Families in Gene Neighborhoods
June 2015
Ryanodine Receptor
April 2015
CCR5 and HIV Infection
January 2015
Drug Targets: Bile Acids in Motion
September 2014
Drug Targets: S1R's Ligands and Partners
September 2014
P2Y Receptors and Blood Clotting
September 2014
Bacterial CDI Toxins
June 2014
Glucagon Receptor
April 2014
March 2014
Microbial Pathogenesis: Targeting Drug Resistance in Mycobacterium tuberculosis
February 2014
Design and Discovery: Virtual Drug Screening
January 2014
Cancer Networks: IFI16-mediated p53 Activation
November 2013
G Proteins and Cancer
November 2013
Drug Discovery: Antidepressant Potential of 6-NQ SERT Inhibitors
October 2013
Drug Discovery: Finding Druggable Targets
October 2013
Drug Discovery: Identifying Dynamic Networks by CONTACT
October 2013
Drug Discovery: Modeling NET Interactions
October 2013
Membrane Proteome: GPCR Substrate Recognition and Functional Selectivity
August 2013
Infectious Diseases: Determining the Essential Structome
May 2013
NDM-1 and Antibiotics
May 2013
Microbial Pathogenesis: Computational Epitope Prediction
January 2013
Microbial Pathogenesis: Influenza Inhibitor Screen
January 2013
Microbial Pathogenesis: Measles Virus Attachment
January 2013
Cytochrome Oxidase
November 2012
Membrane Proteome: The ABCs of Transport
November 2012
Bacterial Phosphotransferase System
October 2012
Regulatory insights
September 2012
Solute Channels
September 2012
Pocket changes
July 2012
Receptor bias
July 2012
Anthrax Stealth Siderophores
June 2012
G Protein-Coupled Receptors
May 2012
Substrate specificity sleuths
April 2012
Reading out regioselectivity
December 2011
Superbugs and Antibiotic Resistance
December 2011
Terminal activation
December 2011
A change to resistance
November 2011
Docking and rolling
October 2011
Breaking down the defenses
September 2011
A2A Adenosine Receptor
May 2011
Cell wall recycler
May 2011
Subtly different
March 2011
January 2011
Subtle shifts
January 2011
ABA receptor diversity
November 2010
COX inhibition: Naproxen by proxy
November 2010
Zinc Transporter ZntB
July 2010
Peptidoglycan binding: Calcium-free killing
June 2010
Treating sleeping sickness
May 2010
Bacterial spore kinase
April 2010
Antibiotics and Ribosome Function
March 2010
Safer Alzheimer's drugs?
March 2010
Anthrax evasion tactics
September 2009
GPCR subunits: Separate but not equal
September 2009
Antibiotic target
August 2009
Salicylic Acid Binding Protein 2
August 2009
July 2009
Tackling influenza
June 2009
Bacterial Leucine Transporter, LeuT
May 2009
Anthrax stealth molecule
March 2009
Drug targets to aim for
February 2009
High-energy storage system
February 2009
Transporter mechanism in sight
February 2009
Scavenger Decapping Enzyme DcpS
November 2008
Blocking AmtB
September 2008

Research Themes Drug discovery

A change to resistance

SBKB [doi:10.1038/sbkb.2011.47]
Featured Article - November 2011
Short description: Two structures of NDM-1 β-lactamase show how this enzyme can confer resistance to many antibiotics.

The active site of NDM-1, in which many of the residues responsible for substrate binding and catalysis are on flexible loops. Image courtesy of Jim Sacchettini.

The most widely used family of antibiotics, the β-lactams, have been a mainstay of clinical therapy since the discovery of penicillin in the early twentieth century. However, pathogenic bacteria have countered the widespread use of β-lactams through the continual adaptation of β-lactamase enzymes that catalyze their hydrolysis. In particular, the recently discovered New Delhi metallo-β-lactamase (NDM-1) enzyme has raised public health concern, as it confers resistance to all known β-lactam antibiotics, including the carbapenem class of β-lactams, which are generally considered the last line of defense. As part of the PSI MTBI partnership, Sacchetini (University of Texas Medical Branch), Joachimiak (PSI MCSG) and colleagues report two crystal structures of NDM-1 that explain this enzyme's broad substrate activity and may help in the future design of NDM-1 inhibitors.

The structures of NDM-1 show that its ability to hydrolyze many β-lactam substrates is due to its large and flexible active site. Compared to other metallo-β-lactamases, the active site of NDM-1 is 2 to 13 times larger in volume. This expanded size stems in part from the conformation of two active site loops, ASL1 and ASL4. In other metallo-β-lactamases these loops bridge over the active sites, whereas in NDM-1 they seem to be splayed outward, leading to a more open conformation of the active site and allowing greater access to potential substrates. Furthermore, amino acid substitutions in these loops, particularly in ASL1, allow them greater flexibility in correctly positioning a broad range of β-lactams for hydrolysis.

By capturing NDM-1 in both the apo and singly zinc-bound forms, the researchers have also shed insight into the catalytic mechanism of β-lactam inactivation. The structures suggest that NDM-1 can exist in three states, defined by whether the enzyme is bound to zero, one or two metals, and that hydrolysis of the β-lactam ring is facilitated by the activation of a zinc-bound water molecule. This mechanism is similar to that described for other metallo-β-lactamases, and may provide a basis for targeting other enzymes of the same family.

In conclusion, the structures of NDM-1 may contribute to the rational design of new drugs capable of treating bacteria that have acquired broad-spectrum antibiotic resistance.

Timothy Silverstein


  1. Y. Kim et al. Structure of apo- and monometalated forms of NDM-1—a highly potent carbapenem-hydrolyzing metallo-β-lactamase.
    PLoS ONE 6, e24621 (2011). doi:10.1371/journal.pone.0024621

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