Untitled

Lim, Daniel; Park, H.U; Castro, Liza de; Kang, Sung-Min; Lee, H.S; Jensen, Susan E.; Lee, K.J; Strynadka, N.C.J.

doi:10.1038/nsb1001-848

Cited by 93 publications

(56 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The Phaser program from the CCP4 package was utilized for molecular replacement (57,58). The BLIP-II molecule from the BLIP-II-TEM-1 structure (Protein Data Bank code 1JTD) was used as the reference molecule (28). After phasing, six molecules per asymmetric unit were found, and the model was fitted to the electron density using Coot (59).…”

Section: Methodsmentioning

confidence: 99%

“…The symmetry of data was found to be C2 with one complex in the asymmetric unit. The initial model was obtained by molecular replacement (MolRep in CCP4 package) search using the BLIP-II model extracted from Protein Data Bank code 1JTD and a preliminary x-ray crystal structure of Bla1 (data not shown) (28,65). Simulated annealing in Refmac5 was performed for the initial refinement, and the structure was then subjected to several rounds of refinement in the Coot program and Refmac5 using TLS restraints (59,63).…”

Section: Methodsmentioning

confidence: 99%

“…In the BLIP-II co-crystal structure with TEM-1, BLIP-II was shown to use these ␤-turns and loops to bind to the same loophelix region of ␤-lactamase as that bound by BLIP. This interaction sterically blocks the active site (28). Previously, we demonstrated that BLIP-II inhibits all six of the class A ␤-lactamases we examined with low picomolar affinity, which is more potent than BLIP-mediated inhibition (46).…”

mentioning

confidence: 99%

“…For example, RCC-1 is a guanine nucleotide exchange factor for the Ran GTPase and is involved in nucleocytoplasmic transport (45). Interestingly, RCC-1 shares 21% sequence identity with BLIP-II and is the founding member of the RCC1-like repeat ␤-propellers (28).…”

mentioning

confidence: 99%

“…Instead, BLIP-II forms an unusual seven-bladed ␤-propeller-fold with three ␤-strands and one ␣-helix per blade. It is believed to function in the S. exfoliatus sporulation process by potentially binding to peptidoglycan remodeling proteins such as penicillin-binding proteins (28). ␤-Propeller domains are ubiquitous among prokaryotes and eukaryotes and govern some of the most critical processes in the cell (42)(43)(44).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Analysis of the Binding Forces Driving the Tight Interactions between β-Lactamase Inhibitory Protein-II (BLIP-II) and Class A β-Lactamases

Brown¹,

Chow²,

Sankaran

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

␤-Lactamases hydrolyze ␤-lactam antibiotics to provide drug resistance to bacteria. ␤-Lactamase inhibitory protein-II (BLIP-II) is a potent proteinaceous inhibitor that exhibits low picomolar affinity for class A ␤-lactamases. This study examines the driving forces for binding between BLIP-II and ␤-lactamases using a combination of presteady state kinetics, isothermal titration calorimetry, and x-ray crystallography. The measured dissociation rate constants for BLIP-II and various ␤-lactamases ranged from 10 ؊4 to 10 ؊7 s ؊1 and are comparable with those found in some of the tightest known protein-protein interactions. The crystal structures of BLIP-II alone and in complex with Bacillus anthracis Bla1 ␤-lactamase revealed no significant side-chain movement in BLIP-II in the complex versus the monomer. The structural rigidity of BLIP-II minimizes the loss of the entropy upon complex formation and, as indicated by thermodynamics experiments, may be a key determinant of the observed potent inhibition of ␤-lactamases.Protein-protein interactions govern many cellular processes, and an understanding of the determinants of molecular recognition would facilitate the rationale design of interactions for therapeutic purposes. Detailed examination of kinetic constants and thermodynamic driving forces, however, has been performed for relatively few protein-protein interaction complexes. Although significant progress has been made in the understanding and prediction of association rate constants, the determinants of dissociation rates remain poorly understood (1-5). The ability to predict the kinetic constants would be a significant contribution to the understanding of interaction networks in the systems biology era (6). Several model systems have been developed to analyze the principles of protein-protein interactions, and one such model is the interaction between ␤-lactamase enzymes and a set of ␤-lactamase inhibitory proteins (BLIPs) 3 (7, 8). ␤-Lactamases act by hydrolyzing the four-membered ring of ␤-lactam antibiotics, e.g. penicillins and cephalosporins, rendering the drugs inactive (9, 10). There are four classes of ␤-lactamases (A-D) based on primary amino acid sequences (11,12). Class B ␤-lactamases are metalloenzymes that use a zinc-coordinated catalytic water to hydrolyze the ␤-lactam ring whereas classes A, C, and D are serine hydrolyases (13-15). Class A ␤-lactamases are widespread in both Gram-positive and Gramnegative bacteria and exhibit broad substrate hydrolysis profiles that include penicillins, cephalosporins, and for a few enzymes, carbapenems (12,14).The catalytic mechanism of serine ␤-lactamases is divided into two stages, acylation and deacylation (16). In class A enzymes, the catalytic Ser-70 residue nucleophilically attacks the carbonyl of the ␤-lactam and forms an acyl-intermediate (17,18). An essential Glu-166 residue activates a highly coordinated water for deacylation (18,19). Substitutions at Glu-166 result in an acylated, inactive enzyme (20 -22).Clinically available mechanism-based inhibitor...

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Analysis of the Binding Forces Driving the Tight Interactions between β-Lactamase Inhibitory Protein-II (BLIP-II) and Class A β-Lactamases

Brown¹,

Chow²,

Sankaran

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

Hemopexin Domains

Gomis-R��th¹

2004

Handbook of Metalloproteins

View full text Add to dashboard Cite

The mammalian serum glycoprotein hemopexin is engaged in the metabolism of heme and in the protection against oxidative stress. It is the lead structure of the hemopexin domains, which are made up of several hemopexin‐type repeats of about 40 residues. Such domains are also found as C‐terminal domains in matrix metalloproteinases, zinc‐dependent hydrolases belonging to the metzincin clan of metalloproteinases. In these proteases, they deal with protein–substrate and protein–inhibitor interactions and in activation events. Both protein classes have been characterized at three‐dimensional structural level. Moreover, hemopexin domains are present within vitronectins, extracellular matrix glycoproteins. In this case, similarity with the former has been just based on sequence information. The presence of hemopexin domains in hemopexins, vitronectins, and matrix metalloproteinases' C‐terminal domains suggests that these repeating peptide motifs have arisen by divergent evolution.

show abstract

X‐Ray Crystallography in Drug Discovery

Livingston¹,

Buchanan²,

D’Amico³

et al. 2003

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

The focus of this chapter is the methods, recent advances, and the applications of X‐ray protein crystallography in the discovery of new drug targets and candidate drugs. It begins with a basic description of the various steps involved in solving a structure, including recent advances in technique and technology, and the major challenges that are faced in executing the process. The underlying theory, various crystallization methods, data collection equipment and techniques, and computational reduction of the data to give the final structure are all covered in this section. The accessible databases that contain large collections of structures are also described. The application to drug discovery is then briefly addressed with a discussion of co‐crystallization methods and issues, which is followed by a comprehensive table enumerating the published structures of the known drug targets and close homologs. Applications to discovering and validating protein targets of therapeutic relevance are then covered in a section on the very new field of structural genomics. Genome annotation by structural homology, elucidating pathways and the potential for the rational design of multitarget drugs, and advances in the field of protein structure modeling that are enabled by crystallographic databases are described and exemplified with very recent results from the field.

show abstract

Untitled

Cited by 93 publications

References 26 publications

Analysis of the Binding Forces Driving the Tight Interactions between β-Lactamase Inhibitory Protein-II (BLIP-II) and Class A β-Lactamases

Analysis of the Binding Forces Driving the Tight Interactions between β-Lactamase Inhibitory Protein-II (BLIP-II) and Class A β-Lactamases

Hemopexin Domains

X‐Ray Crystallography in Drug Discovery

Contact Info

Product

Resources

About