The crystal structures of PKG Iβ (92-227) with cGMP and cAMP reveal the molecular details of cyclic-nucleotide binding

Journal Article · Mon Aug 01 00:00:00 EDT 2011 · BMC Pharmacology

DOI:https://doi.org/10.1186/1471-2210-11-S1-O14· OSTI ID:1629607

Kim, Jeong Joo ^[1]; Casteel, Darren E. ^[2]; Huang, Gilbert ^[3]; Kwon, Taek Hun ^[4]; Ren, Ronnie Kuo ^[5]; Zwart, Peter ^[6]; Headd, Jeffrey J. ^[6]; Brown, Nicholas Gene ^[3]; Chow, Dar-Chone ^[3]; Palzkill, Timothy ^[7]; Kim, Choel ^[8]

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1. Baylor Univ., Houston, TX (United States). Dept. of Pharmacology; DOE/OSTI
2. Univ. of California, San Diego, CA (United States). Dept. of Medicine
3. Baylor Univ., Houston, TX (United States). The Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology
4. Baylor Univ., Houston, TX (United States). Dept. of Pharmacology
5. Rice Univ., Houston, TX (United States)
6. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). The Berkeley Center for structural Biology
7. Baylor Univ., Houston, TX (United States). Dept. of Pharmacology; Baylor Univ., Houston, TX (United States). The Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology; Baylor Univ., Houston, TX (United States). College of Medicine. Dept. of Molecular Virology and Microbiology
8. Baylor Univ., Houston, TX (United States). Dept. of Pharmacology; Baylor Univ., Houston, TX (United States). The Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology

Cyclic GMP is a crucial second messenger that translates extracellular signals into a variety of cellular responses. As a central mediator of the Nitric Oxide-cGMP signalling cascade, which regulates vascular tone, platelet aggregation, nociception and hipocampal/cerebellar learning, Cyclic GMP-dependent protein kinases (PKGs) represents an important drug target for treating hypertensive diseases and erectile dysfunction. The fidelity of the NO-cGMP signaling pathway is largely dependent on PKG’s ability to selectively bind cGMP over cAMP. Although both cGMP and cAMP bind and activate PKG, cGMP preferentially activates PKG 60-100 fold better than cAMP; yet, little is known about the molecular features required for the cGMP selectivity of PKG. We have investigated the mechanism of cyclic nucleotide binding to PKG by determining crystal structures of the amino-terminal cyclic nucleotide-binding domain (CNBD-A) of human PKG I bound to either cGMP or cAMP. We also determined the structure of CNBD-A in the absence of bound nucleotide.

• Research Organization: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
• Sponsoring Organization: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
• Grant/Contract Number: AC02-05CH11231
• OSTI ID: 1629607
• Journal Information: BMC Pharmacology, Journal Name: BMC Pharmacology Journal Issue: S1 Vol. 11; ISSN 1471-2210
• Publisher: BioMed Central
• Country of Publication: United States
• Language: English

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