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Structural Basis of...
Structural Basis of Inhibition of Insulin-Regulated Aminopeptidase by a Macrocyclic Peptidic Inhibitor
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- Mpakali, Anastasia (författare)
- Natl Ctr Sci Res Demokritos, Athens 15341, Greece.
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- Saridakis, Emmanuel (författare)
- Natl Ctr Sci Res Demokritos, Athens 15341, Greece.
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- Giastas, Petros (författare)
- Natl Ctr Sci Res Demokritos, Athens 15341, Greece.
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- Maben, Zachary (författare)
- Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01655 USA.
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- Stern, Lawrence J. (författare)
- Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01655 USA.
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- Larhed, Mats (författare)
- Uppsala universitet,Institutionen för läkemedelskemi,Science for Life Laboratory, SciLifeLab
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- Hallberg, Mathias, 1971- (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Stratikos, Efstratios (författare)
- Natl Ctr Sci Res Demokritos, Athens 15341, Greece.
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Natl Ctr Sci Res Demokritos, Athens 15341, Greece Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01655 USA. (creator_code:org_t)
- 2020-06-02
- 2020
- Engelska.
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Ingår i: ACS Medicinal Chemistry Letters. - : AMER CHEMICAL SOC. - 1948-5875. ; 11:7, s. 1429-1434
- Relaterad länk:
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https://www.ncbi.nlm...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Insulin-regulated aminopeptidase (IRAP) is a transmembrane zinc metallopeptidase with many important biological functions and an emerging pharmacological target. Although previous structural studies have given insight on how IRAP recognizes linear peptides, how it recognizes its physiological cyclic ligands remains elusive. Here, we report the first crystal structure of IRAP with the macrocyclic peptide inhibitor HA08 that combines structural elements from angiotensin IV and the physiological substrates oxytocin and vasopressin. The compound is found in the catalytic site in a near canonical substrate-like configuration and inhibits by a competitive mechanism. Comparison with previously solved structures of IRAP along with smallangle X-ray scattering experiments suggests that IRAP is in an open conformation in solution but undergoes a closing conformational change upon inhibitor binding. Stabilization of the closed conformation in combination with catalytic water exclusion by the tightly juxtaposed GAMEN loop is proposed as a mechanism of inhibition.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- Enzyme
- inhibitor
- X-ray crystallography
- small-angle X-ray diffraction
- aminopeptidase
- mechanism
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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