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Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase

Davis, Mindy I. and Bennett, Melanie J. and Thomas, Leonard M. and Bjorkman, Pamela J. (2005) Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase. Proceedings of the National Academy of Sciences of the United States of America, 102 (17). pp. 5981-5986. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:DAVpnas05

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Abstract

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer cells and nonprostatic solid tumor neovasculature and is a target for anticancer imaging and therapeutic agents. PSMA acts as a glutamate carboxypeptidase (GCPII) on small molecule substrates, including folate, the anticancer drug methotrexate, and the neuropeptide N-acetyl-l-aspartyl-l-glutamate. Here we present the 3.5-Å crystal structure of the PSMA ectodomain, which reveals a homodimer with structural similarity to transferrin receptor, a receptor for iron-loaded transferrin that lacks protease activity. Unlike transferrin receptor, the protease domain of PSMA contains a binuclear zinc site, catalytic residues, and a proposed substrate-binding arginine patch. Elucidation of the PSMA structure combined with docking studies and a proposed catalytic mechanism provides insight into the recognition of inhibitors and the natural substrate N-acetyl-l-aspartyl-l-glutamate. The PSMA structure will facilitate development of chemotherapeutics, cancer-imaging agents, and agents for treatment of neurological disorders.


Item Type:Article
Additional Information:Contributed by Pamela J. Bjorkman, March 15, 2005. Freely available online through the PNAS open access option. We thank members of the Bjorkman laboratory for technical assistance and critical reading of the manuscript, Doug Rees and Michael Chan for helpful discussions, the staff at Stanford Synchrotron and Radiation Laboratory and Advanced Light Source for assistance with synchrotron data collection, Adam Paiz for help with crystallization, Peter Snow and Inder Nangiana of the California Institute of Technology Protein Expression Facility for protein expression, Gary Hathaway of the California Institute of Technology Protein/Peptide Microanalysis Facility for mass spectrometry and N-terminal sequencing, Jens Kaiser for assistance with main and the zinc patch, David Mathog of the California Institute of Technology Sequence and Structure Analysis Facility for help with sequence alignments, and Tomas Bzdega and Joseph Neale (Georgetown University, Washington, DC) for the PSMA gene. This work was supported by a Department of Defense Prostate Cancer Postdoctoral Award (to M.I.D.), an American Liver Foundation Postdoctoral Award (to M.I.D.), and the Howard Hughes Medical Institute (to P.J.B.). Author contributions: M.I.D., M.J.B., and P.J.B. designed research; M.I.D. performed research; M.I.D., M.J.B., and P.J.B. analyzed data; M.I.D., M.J.B., and P.J.B. wrote the paper; and L.M.T. assisted with data collection and initial structure solution. Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 1Z8L). Supplementary material: http://pubmedcentral.gov/picrender.fcgi?artid=556220&blobname=pnas_102_17_5981__.html
Subject Keywords:crystallography, folate hydrolase, glutamate carboxypeptidase II, Naaladase I Abbreviations: PSMA, prostate-specific membrane antigen; AAP, A. proteolytica aminopeptidase; AMP1, A. thaliana PSMA; CPG2, carboxypeptidase G2; α-NAAG, N-acetyl-l-aspartyl-l-glutamate; NLD, Naaladase; PepT, peptidase T; PepV, peptidase V; Sgap, S. griseus aminopeptidase; TfR, transferrin receptor.
Record Number:CaltechAUTHORS:DAVpnas05
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:DAVpnas05
Alternative URL:http://dx.doi.org/10.1073/pnas.0502101102
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:329
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:01 Jun 2005
Last Modified:14 Nov 2014 19:18

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