A Leukotriene A4 Hydrolase-Related Aminopeptidase from Yeast Undergoes Induced Fit upon Inhibitor Binding

Helgstrand, Charlotte; Hasan, Mahmudul; Uysal, Hüseyin; Haeggström, Jesper Z.; Thunnissen, Marjolein M.G.M.

doi:10.1016/j.jmb.2010.11.059

Cited by 9 publications

(5 citation statements)

References 44 publications

(50 reference statements)

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“…The presence of bestatin may therefore be due to altered affinities of the inhibitor in the two different crystallization conditions, which differ significantly in pH and composition. Recently, Thunnissen et al proposed such a mechanism for the yeast ortholog of LTA4H (26), although the described structural rearrangements do not apply to ERAP1 and the resulting domain movements are very different for the two proteins. Either way, the presence of an additional site of interaction would favor longer peptide substrates by an increase in the overall binding energy and/or by increasing the local concentration of free N termini, thus increasing their binding propensity into the active site.…”

Section: Resultsmentioning

confidence: 99%

Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming

Kochan

Krojer

Harvey

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

231

286

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Endoplasmatic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme involved in trimming of peptides to an optimal length for presentation by major histocompatibility complex (MHC) class I molecules. Polymorphisms in ERAP1 have been associated with chronic inflammatory diseases, including ankylosing spondylitis (AS) and psoriasis, and subsequent in vitro enzyme studies suggest distinct catalytic properties of ERAP1 variants. To understand structure-activity relationships of this enzyme we determined crystal structures in open and closed states of human ERAP1, which provide the first snapshots along a catalytic path. ERAP1 is a zinc-metallopeptidase with typical H-E-X-X-H-ðXÞ 18 -E zinc binding and G-A-M-E-N motifs characteristic for members of the gluzincin protease family. The structures reveal extensive domain movements, including an active site closure as well as three different open conformations, thus providing insights into the catalytic cycle. A K 528 R mutant strongly associated with AS in GWAS studies shows significantly altered peptide processing characteristics, which are possibly related to impaired interdomain interactions.antigen presentation | ERAP1 mechanism | MHC restriction

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Section: Resultsmentioning

confidence: 99%

Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming

Kochan

Krojer

Harvey

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

231

286

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show abstract

“…It follows that substrate-dependent loop ordering and the observed plasticity may reflect a requirement for broad specificity at the P1 position of the bound substrate. Notably, differences in the conformation of a single side chain in the S1 site have served to accommodate different N-terminal amino acids in other M1 family members (31,32,54). In addition to its role in processing AngIII and AngIV, hAPN has a number of other physiological peptide substrates and it shows relatively broad specificity when assayed with amino acid analogues (39).…”

Section: Discussionmentioning

confidence: 99%

The X-ray Crystal Structure of Human Aminopeptidase N Reveals a Novel Dimer and the Basis for Peptide Processing

Wong

Zhou

Rini

2012

Journal of Biological Chemistry

121

217

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Background: Human aminopeptidase N (hAPN) is a dimeric cell surface protease involved in peptide processing, cell adhesion, endocytosis, and signal transduction. Results: Crystal structures of peptide and inhibitor complexes were determined. Conclusion: Unlike other family members, hAPN shows substrate-dependent loop ordering and a novel dimer structure. Significance: A model for catalysis and conformational changes provides mechanistic insights into how hAPN mediates its functional roles.

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“…Interestingly in our study, relaxation of the crystal contacts also produced an increase in size of the S1 substrate pocket that immediately resulted in fluctuations in the position of the Phe ring. Rotation of the Phe ring when bestatin is bound is also not unique to Pf A‐M1, as other crystal structures have identified different positions of the Phe ring . Positioning of the Phe ring relies on π–π stacking in Pf A‐M1 as well as in porcine aminopeptidase N and the human aminopeptidase A .…”

Section: Discussionmentioning

confidence: 98%

“…With the exception of APN, the bestatin‐bound M1 aminopeptidases show a conserved binding mode wherein the backbone hydroxy ketone of bestatin coordinates the active site zinc ion . In APN, it is the terminal carboxylic acid that coordinates the zinc, which results in a completely different binding pose .…”

Section: Discussionmentioning

confidence: 99%

Mapping the Pathway and Dynamics of Bestatin Inhibition of the Plasmodium falciparum M1 Aminopeptidase PfA‐M1

et al. 2018

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The M1 metallo‐aminopeptidase from Plasmodium falciparum, PfA‐M1, is an attractive drug target for the design of new antimalarials. Bestatin, a broad‐spectrum metalloprotease inhibitor, is a moderate inhibitor of PfA‐M1, and has been used to provide structure–activity relationships to inform drug design. The crystal structure of PfA‐M1 with bestatin bound within its active site has been determined; however, dynamics of the inhibitor and the association or dissociation pathway have yet to be characterized. Here we present an all‐atom molecular dynamics study where we have generated a hidden Markov state model from 2.3 μs of molecular dynamics simulation. Our hidden Markov state model identifies five macrostates that clearly show the events involved in bestatin dissociation from the PfA‐M1 active site. The results show for the first time that bestatin can escape the substrate specificity pockets of the enzyme, primarily due to weak interactions within the pockets. Our approach identifies relevant conformational sampling of the inhibitor inside the enzyme and the protein dynamics that could be exploited to produce potent and selective inhibitors that can differentiate between similar members of the M1 aminopeptidase superfamily.

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A Leukotriene A4 Hydrolase-Related Aminopeptidase from Yeast Undergoes Induced Fit upon Inhibitor Binding

Cited by 9 publications

References 44 publications

Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming

Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming

The X-ray Crystal Structure of Human Aminopeptidase N Reveals a Novel Dimer and the Basis for Peptide Processing

Mapping the Pathway and Dynamics of Bestatin Inhibition of the Plasmodium falciparum M1 Aminopeptidase PfA‐M1

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